IMMpact Report - UTHealth
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M C G O V E R N M E D I C A L S C H O O L’ S B ROW N F O U N D AT I O N I N S T I T U T E o f M O L E C U L A R M E D I C I N E F O R T H E P R E V E N T I O N of H U M A N D I S E A S E S IMMpact Report FISCAL YEAR 2018
About the cover The stunning interior architecture of McGovern Medical School’s Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases. IMMpact Report is published by McGovern Medical School. All correspondence should be addressed to: Office of Communications 6431 Fannin, B.340 Houston, TX 77030 E-mail: m.darla.brown@uth.tmc.edu Articles and photos may be reprinted with permission. Editor Darla Brown, Director, Office of Communications Contributors: Darla Brown Jonathan Garris John Kriescher IMM Faculty Design: Roy Prichard Photography: Dwight Andrews Lorenz Meyer
The University of Texas Health Science Center at Houston (UTHealth) Leadership Giuseppe N. Colasurdo, M.D. President Kevin Dillon, M.B.A., C.P.A. Senior Executive Vice President, Chief Operating & Financial Officer Michael Blackburn, Ph.D. Executive Vice President, Chief Academic Officer Barbara J. Stoll, M.D. Dean, McGovern Medical School IMM Senior Administrator John F. Hancock, M.A., M.B., BChir., Ph.D., Sc.D. Executive Director IMM Advisory Council Members Mr. John E. McDonald, Chair Mr. Alan P. Baden Regent David J. Beck Mr. John Barney Beckworth Mrs. Louana H. Frois Mr. Theodore M. Frois Irma Gigli, M.D. Mr. Steven L. Gordon Dr. John F. Hancock Mr. John Mackel III Mr. Rodney H. Margolis Mr. D. Bradley McWilliams Mr. D. Dudley Oldham Mr. Charles R. Parker Mrs. Judy Perkins Ms. Beth Robertson Mr. Clive Runnells Shavonnah Roberts Schreiber, M.B.A., P.C.M. Mr. Ralph B. Thomas The University of Texas System Board of Regents Sara Martinez Tucker, Chairman Jeffery D. Hildebrand, Vice Chairman Paul L. Foster, Vice Chairman Ernest Aliseda David J. Beck Kevin P. Eltife R. Steven Hicks Brittany E. Jewell Janiece Longoria James C. “Rad” Weaver
Contents
2 Director's Message Features
3 Mission
4 Our Locations
6 8
16 Center for Cardiovascular Genetics Harnessing the power
of proteomics in Finding pharma
19 Center for Human Genetics disease research at home
25 Center for Immunology and Autoimmune Diseases
31 Center for Metabolic and Degenerative Diseases
40 Center for Molecular Imaging 10 12
Uncovering the Understanding
46 Center for Precision Biomedicine mysteries of disease risks encoded
neurodegenerative within our
53 Center for Stem Cell and Regenerative Medicine diseases non-coding genomes
70 Center for Tissue Engineering and Aging Research
77 Texas Therapeutics Institute
86 IMM Service Centers 15
IMMPACT REPORT
A catalyst
88 By the Numbers for change
90 Gift Report
••••
1
Director’s Message
I
’m pleased to introduce the latest annual IMMpact report for The Brown
Foundation Institute of Molecular Medicine for the Prevention of Hu-
man Diseases (IMM). The IMM is a stand-alone research institute that is
embedded within McGovern Medical School. The IMM mission is to deliver
translational outcomes from research in molecular medicine that benefits
patients. To this end, we have teams of outstanding basic and translational
scientists who collaborate closely with our clinical colleagues. Inside the re-
port you will find in-depth articles on some of our faculty and donors plus an
account from each IMM faculty member describing their research programs.
This year we have recruited additional outstanding new faculty, who
bring with them exciting research ideas and innovative technologies. One of
our new recruits, whose story is featured, also secured a prestigious STAR
award from The University of Texas System, which are reserved for the
recruitment of highly sought-after scientists. The environment for scientific
research funding continues to be extremely challenging, especially from the
NIH. Despite this, IMM faculty have excelled again. Over the financial
The IMM has year just ended, our new grants and contracts were up some 20 percent over
the preceding year, which in turn had seen a considerable increase over the
two major prior year. Indeed, we have now substantially increased our extramural grant
objectives: funding for each of the last six years! It is a testament to the remarkable
quality and creativity of our scientists that the IMM remains so successful
in attracting research funds from what is an ever-diminishing national pool.
1 Discovery is the That said, full implementation of our mission remains heavily dependent on
highest priority for attracting support from alternative sources, including research charities and
the IMM faculty. This foundations, industry collaborations, and, most importantly, the continuing
is a major challenge, generosity of our friends and donors.
since diabetes, obesity, In addition to advancing science and medicine, we therefore wish to
cancer, Alzheimer’s, and develop our relationships with all in our community who value the aspira-
cardiovascular diseases tion of our mission to translate molecular discoveries into new therapies
are unsolved medical for human disease. In this regard, we are deeply appreciative of the strong
problems that are not work and dedication of the IMM advisory council, which plays a key role in
the continued growth and development of the IMM. If you would like to
caused by single gene
investigate how you can also be involved, I would be pleased to talk with you
defects. Discoveries lead
personally. Alternatively, I would be delighted to see you at our annual IMM
to new solutions.
symposium. Last year, 165 guests listened to two talks in the Beth Robert-
son Auditorium and attended a reception in the James T. Willerson, M.D.
2 New diagnostics and Discovery Hall. This year the symposium will be held on May 1, 2019, and
therapies are derivative will feature talks on obesity and diabetes, answering questions about appetite,
of discovery and to the why we feel hungry and stop eating (or not!), and how we burn and use the
benefit of patients. The calories that we eat. It will be a very illuminating and entertaining evening.
IMM focuses on these As with last year we will have an extended question time with an expert panel
medical solutions. The comprising the speakers plus UTHealth physicians. The symposium is an ex-
IMM has organized cellent opportunity to hear exciting research stories directly from our faculty,
talent in the Texas to discuss its implications for the future of medicine and health care, and to
Therapeutics Institute have all your questions answered. Full details are in this report; please mark
specifically to achieve the date in your calendar because it is a great opportunity to visit the IMM.
IMMPACT REPORT
this goal of patient
John Hancock, M.A., M.B., B.Chir., Ph.D., Sc.D.
benefit from discovery.
Executive Director, Institute of Molecular Medicine
John S. Dunn Distinguished University Chair in Physiology and Medicine
••••
2
Mission
T
he Brown Foundation research and the future practice to medical practice are of
Institute of Molecular of medicine with more novel major importance to product
Medicine for the therapies. These approaches development in biotechnology
Prevention of Human Diseases have been most successfully and the pharmaceutical
(IMM) is a research institute used to determine the causes of industry, the IMM has
that seeks to investigate the infectious disorders and genetic the potential and desire to
causes of human diseases at diseases. form important links and
the cellular and molecular However, it is clear that collaborations between its
levels, using DNA and protein molecular and cell biology own research activities and
technologies to elucidate disease will play a major role in various industries to apply its
mechanisms. This development clarifying the causes of many discoveries and intellectual
and progress are of particular unsolved problems of modern properties to pharmaceutical
interest for future planning medicine, such as heart opportunities.
in the increasingly important disease, hypertension, vascular As an institute of McGovern
area of clinical research. The disorders, major mental Medical School, the Brown
institute endeavors to design illnesses, and inflammatory Foundation Institute of
methods of rational therapy and immunologic diseases. Molecular Medicine for the
and, wherever possible, The research of the institute’s Prevention of Human Diseases
strategies for the prevention of investigators is inspiring and strives to set the example
human diseases. promises to fulfill the mission for research excellence and
IMMPACT REPORT
Advances in molecular and of the IMM. collaboration locally, nationally,
cell biology have enormous Because the applications and internationally.
potential for innovative medical of molecular and cell biology
••••
3
Our Locations
Fayez S. Sarofim Research Building
• Primary home of the IMM’s faculty,
administration, and support staff.
• Located adjacent to the The University of
Texas Health Science Center at Houston
(UTHealth) University Center Tower within
the Texas Medical Center.
• Opened in 2006, the building encompasses
255,748 gross square feet.
South Campus Research Building – 3 (SCRB3)
• SCRB3 is a collaboration between The
University of Texas MD Anderson Cancer
Center and UTHealth, in cooperation with
GE Healthcare and the Texas Enterprise Fund.
• Six-stories, 315,000 square-feet located on the
South Campus of the Texas Medical Center.
• Opened in 2009, this facility houses Positron
Emission Tomography, Magnetic Resonance
Imaging, Optical Imaging Tracers, a
Cyclotron, wet labs, and support offices.
The Denton A. Cooley Building – Texas Heart Institute
at St. Luke’s Episcopal Hospital
• The IMM occupies a 31,000 square-foot high-
tech laboratory.
• Located in the Texas Medical Center.
IMMPACT REPORT
••••
4
The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases
IMMpact Symposium
Fayez S. Sarofim Research Building
1825 Pressler Street
Wednesday, May 1, 2019 SAVE THE DATE
4:00 - 6:30 pm
Weighing in on the Science of Staying Slim
To eat or not to eat: Demand-side economics
It’s all in your brain of blood sugar:
Use it to lose it
Dr. Qingchun Tong, Ph.D.
Associate Professor
Dr. Rebecca Berdeaux, Ph.D.
Cullen Chair in Molecular Medicine
Associate Professor
Center for Metabolic and Degenerative
IMMPACT REPORT
Center for Metabolic and Degenerative
Disease
Disease
••••
5
Profiles in research
Harnessing the power of
proteomics in disease research
W
ith genetic testing “Proteomics has become a to become the second leading
gone mainstream, mainstay in basic, translational, cause of cancer death by 2030.
knowing our an- and clinical research,” says Dr. “Most patients are third- or
cestry or risk for disease is just Pan, who earned his doctorate fourth-stage when they are di-
a saliva sample or blood draw from the University of Washing- agnosed because of the difficul-
away. ton in Seattle, where he also was ties of diagnosis at early stage.
But did you know that the on faculty for a decade before Moreover, drug resistance to
genetic difference between you joining the IMM in 2017. therapy is a significant challenge
and your neighbor is about 0.1 Scientists rely upon pro- in pancreatic cancer treatment,”
percent? Or that the difference teomics technologies to look at he explains as to why the death
between our genome and that of the protein expression level and rate is so high.
chimps is just 1.2 percent? study mutated sequences and Looking to improve the
Where the greatest biological post-translational modifications. diagnosis and therapeutics of
differences are expressed are at They also examine proteins for pancreatic cancer, Dr. Pan,
the protein level, explains Sheng their interactions with proteins in collaboration with Baylor
Pan, Ph.D., associate profes- or other biomolecules, such as College of Medicine and the
sor in the Center for Precision DNA, and their reactions to University of Washington, is
Biomedicine at The Brown drugs. working on a National Institutes
Foundation Institute of Molecu- “Proteins are the essential of Health grant to study early
lar Medicine for the Prevention functional biomolecules and detection of pancreatic cancer in
of Human Diseases (IMM) at participate in all diseases, so patients with new onset diabetes.
UTHealth. they can be biomarkers for “We know that pancreatic
“Tissue of muscle is differ- diagnosis or potential targets cancer prevalence is higher in
ent from the tissue of the lung for drug therapies,” Dr. Pan this group than in the general
because the proteome – the explains. population, so we are investi-
entire complement of proteins To study the proteome at a gating proteome differences in
expressed by that tissue – is functional level, Dr. Pan and his those who develop cancer and
different,” says Dr. Pan, director team extract proteins from vari- those who do not have cancer
of the Clinical and Translational ous biological and clinical speci- to better understand the disease
Proteomics Service Center. mens to analyze with the mass mechanism and to develop
Proteomics – the study spectrometer. Data from there biomarkers to assist early cancer
of proteins and how they are are translated into biologically detection,” he says.
implicated in disease and health meaningful results using bioin- “We are looking for cancer
– has flourished as an area of formatics. “From a typical tissue associated protein abundance
scientific research and discovery or cell lysate sample, we get changes, protein variances, and
over the last 20 years. In fact, a about 1.5 gigabytes of data,” Dr. post-translational modifications
review of the medical literature Pan explains. “It is a big data using quantitative proteomics,”
reveals a 6,000 percent increase technology. Cutting-edge mass he says. “Our goal is to assist in
in the terms “proteomics and spectrometry is highly sensitive the early detection and interven-
cancer” in published research and accurate – it can determine tion of pancreatic cancer.”
from 2000 to 2017. a molecular mass with one part In addition to his main
Through the Clinical and per million resolution.” research projects on pancreatic
Translational Proteomics Service One specific disease that cancer and GI-tract diseases, Dr.
Center, Dr. Pan and his col- has captured Dr. Pan’s focus is Pan’s lab also supports pro-
IMMPACT REPORT
leagues provide proteomics and pancreatic cancer. The fourth- teomics studies of neurological,
mass spectrometry support to leading cause of cancer deaths in inflammatory, and other diseases
researchers at UTHealth and the United States, Dr. Pan says through collaborative efforts.
throughout the Houston area. that pancreatic cancer is poised
••••
6
IMMPACT REPORT
Dr. Sheng Pan puts proteomic data to work in the fight against cancer.
••••
7IMMPACT REPORT
Dr. Kendra Carmon decided to pursue her scientific career at UTHealth’s IMM.
••••
8Profiles in research
Finding pharma at home
A
rmed with a degree in is co-directed by Zhiqiang An, 50,000. Although mortality
chemical engineering, Ph.D., the Robert A. Welch is declining, new therapies are
Kendra Carmon had Distinguished University Chair needed.
her eyes set on a big pharma in Chemistry, and Dr. Liu, the “We are trying to identify
career following training at Janice D. Gordon Distinguished new drug targets in cancer that
UTHealth. Professor in Bowel Cancer are aimed only at the tumor
And why not? The Research. cells, not normal cells in order
pharmaceutical industry “TTI brings that pharma to decrease side effects,” Dr.
has a massive research and element I was looking for right Carmon explains. “We are also
development component here to UTHealth. Working in looking at the functional role
attractive to bright young Jim’s lab provided the expertise I of LGR5, which is expressed
scientists such as Carmon. was looking for from industry as in cancer stem cells and drives
But a funny thing happened he previously was at Merck and cancer growth.”
on the way to the pharma lab. Lexicon Genetics,” Dr. Carmon Dr. Carmon’s innovative
Carmon completed her explains. work has been recognized with
doctorate at UTHealth in At this time Dr. Carmon a five-year National Institutes
pharmacology and molecular also received high-risk award of Health (NIH) grant to look
biology, working in the lab of funding from the Cancer at the effect of cancer stem cells
David Loose, Ph.D., in the Prevention and Research in eradicating colon cancer
Department of Integrative Institute of Texas (CPRIT), and with a Welch Research
Biology and Pharmacology, which as authorized by the Scholar Award to identify novel
where she worked to create Legislature, provides funding therapeutic targets and elucidate
assays and run drug screens. to Texas-based scientists their role in gastrointestinal
“I intended to move on to expedite innovation in cancers.
into pharma after I graduated, cancer research and product Dr. Carmon says she was
but at that time, the Texas development. The major goal of “lucky” to receive her first NIH
Therapeutics Institute and Dr. this project was to generate anti- Research Project Grant Program
Jim Liu came to the IMM, LGR5 antibody-drug conjugates (R01) so early in her career.
and I started learning more that target and eradicate LGR5- However, she also states that
about drug discovery right here expressing tumor cells, which “it also takes hard work and
at UTHealth by becoming a are found in cancer stem cells. innovative ideas.”
postdoc in his lab,” she explains. After her postdoc training, A recent study shows that
The Texas Therapeutics Dr. Carmon was invited to join the average age of investigators
Institute (TTI) is a joint the TTI faculty as an instructor receiving such grants has
program of UTHealth, MD in 2012 and was appointed climbed to an all-time high: 46.
Anderson Cancer Center, and assistant professor in 2015. Getting such a head start
the departments of chemistry She continues to focus her means Dr. Carmon is well on
and biochemistry at The research on cancer – specifically her way to her long-term goal of
University of Texas at Austin. colon cancer. creating “practical, translational”
Its goal is to help biomedical Colon cancer is the third- research that will help current
researchers transform their most common cancer in the and future cancer patients.
discoveries into novel United States, with death rates
diagnostics and treatments. It in 2018 expected to reach about
“ We are trying to identify new drug targets in cancer that are
IMMPACT REPORT
aimed only at the tumor cells, not normal cells in order to
decrease side effects.
”
— Dr. Kendra Carmon
••••
9IMMPACT REPORT
Dr. Sheng Zhang’s research could help unlock the key to methods of prevention, and perhaps cures,
for neurodegenerative diseases.
••••
10Profiles in research
Uncovering the mysteries of
neurodegenerative diseases
M
illions of people we already garnered about The faulty Huntingtin protein
across the globe cancer and their treatment builds up gradually and forms
struggle every day options, even at that time, the prominent clumps in the
with debilitating aging-related knowledge and understanding brain, but why this particular
neurodegenerative diseases. about neurodegeneration abnormality leads to the disease
Researchers at the Center for disorders were flatly blank, with is unclear. Researchers found
Metabolic and Degenerative hardly any effective treatment the removal of the Huntingtin
Diseases are aiming to give available,” Dr. Zhang says. “It protein from fruit flies weakens
them a fighting chance against was very enticing for a young them, ages them faster, and
these devastating brain disorders student to plunge into this new they die significantly earlier.
by better understanding the unchartered field.” The protein was found to
culprits responsible for the Dr. Zhang has been be important for the self-
causes and progress of these particularly interested in maintenance of the cell, as it
diseases and identify methods of examining how the abnormal helps clear cellular waste.
prevention and cure. protein clumps develop in the “For the majority of these
Dr. Sheng Zhang, assistant affected brain and how they diseases, there is no clear
professor in the Center, is one of can be effectively cleared. These hereditary pattern or genetic
several researchers at the IMM clumps are often composed of cause,” Dr. Zhang says. “But
studying neurodegenerative faulty proteins directly linked for Huntington’s, there is one
disorders. Dr. Zhang has to diseases like Alzheimer’s gene and one mutation, and
been particularly interested disease, Parkinson’s disease, and this mutation is associated with
in Huntington’s disease amyotrophic lateral sclerosis robust formation of pathogenic
and Parkinson’s disease, the (Lou Gherig’s disease), however clumps.”
two focuses of his study at little is known exactly how such Finding the molecular
McGovern Medical School, in clumps form, and why such a drivers behind this disease and
addition to his collaborative common pathological feature why this particular mutation
project on Alzheimer’s disease can be linked to destruction of causes Huntington’s disease
with colleague Dr. Hui Zheng, different groups of neurons in is a major passion behind Dr.
director of Huffington Center different parts of the brain. Zhang’s research. While there
on Aging at neighboring Baylor “If we can know which are still many unknown factors
College of Medicine. pathway leads to the disease, in the pathogenesis of these
He was first struck there’s a chance we can correct neurodegenerative diseases left
by the idea of pursuing them and may be able to slow to researchers, Dr. Zhang says
neurodegenerative diseases when down, or even cure, the disease,” it’s an exciting time to be in his
he was studying cancer while he Dr. Zhang says. “What’s unique field as researchers are making
was a graduate student at Yale about these neurodegenerative substantial progress.
University School of Medicine. diseases is that patients mostly “This is a major challenge for
Through the use of fruit flies, develop symptoms when they society,” Dr. Zhang says. “People
Dr. Zhang found a gene in this are older, so even just delaying have become more aware of this
small insect that was important the progress of the disease is issue, including Congress and
for its development and has more than enough for most many private organizations and
a highly similar counterpart patients and their loved ones for regular citizens. It’s still too early
in humans that, when the rest of their lifespan.” to say what might happen, but I
IMMPACT REPORT
mutated, causes one of these For example, Huntington’s feel we have moved much closer
neurodegenerative disorders. disease is caused by an abnormal to an answer, and more likely,
“Compared to the expansion of a glutamine tract answers.”
mountains of information in the Huntingtin protein.
••••
11Profiles in research
Understanding disease risks
encoded within our
non-coding genomes
D
r. Ashish Kapoor, as- in this regulatory machinery “Tissues are made from a
sistant professor, may largely underlie common disease mixture of different cell-types,
be relatively new to risk and trait variation. and when you grind up a tis-
McGovern Medical School, but “One thing we as a com- sue, the signals you’re seeing,
he is already looking forward to munity have learned is that whether epigenomic or tran-
working with fellow researchers most of the genetic risk/basis scriptional, are from different
to gain a better understanding for common diseases and traits cell-types,” Dr. Kapoor says. “I
of the role non-coding genomes is not coming from variation think characterization of the
play in the risk of developing in the gene sequences as such non-coding genome on disease-
disease. or what we call the coding part relevant cell-types is going to
Dr. Kapoor joined the IMM of the genome,” Dr. Kapoor be more informative for un-
from Johns Hopkins University says. “It’s coming from variation covering the underlying disease
School of Medicine, where he in the sequences outside the mechanisms.”
completed postdoctoral work in gene-bodies, or what we call the Despite an uphill battle in
the laboratory of Dr. Aravinda non-coding genome.” understanding the intricacies of
Chakravarti. At the IMM, he Among the challenges for the non-coding human genome,
works to understand the role of researchers is that there isn’t Dr. Kapoor says significant
variable gene expression driven a deep understanding of the discoveries have been made.
by non-coding regulatory se- language(s) used by non-coding His lab is working to identify
quence variation in disease risk. genomes. the pieces of the non-coding
How much of a gene product “Compared to the coding genome that regulate gene
is made (expressed) by our cells genome, we have very little expression, focusing on those
varies not only across different understanding of how diverse whose functions are altered
cell-types within an individual functions are encoded in our by disease or trait associated
but also across individuals non-coding genome and the sequence variants. The causal
themselves. This natural vari- impact sequence variation has genes, whose expression levels
ability in gene expression plays on such functions,” Dr. Kapoor are modulated due to regulatory
a major role not only in how says. “Among several functions, variants, are then manipulated
we differ from one another but regulation of gene expression is in model systems (cells and
also in how common diseases a major function of the non- animals) to further assess if they
develop. Dr. Kapoor’s lab uti- coding genome.” lead to a disease or trait relevant
lizes electrocardiographic QT Large-scale efforts like the outcome.
interval as a model trait to bet- Roadmap Epigenomics, the Dr. Kapoor says he is excited
ter understand the mechanisms ENCODE and the GTEx proj- to continue working with his
behind such variances. Much ects are steps in the right direc- colleagues and fellow researchers
of the risk for common diseases tion, but so far such efforts have around the Texas Medical Cen-
emanates from multiple genes been applied largely on a tissue ter and begin specific collabora-
and is due to genetic differences, level. Dr. Kapoor says the key tions.
or variations, outside gene- will be to do similar studies on “Given the broad range of
bodies (non-coding) that likely the level of cell-types and gain skill sets required to carry out
affect expression of those genes. a better understanding of the this kind of research, I am look-
IMMPACT REPORT
In other words, how much specific molecular components ing forward to working with
of a normal gene product is and structure of the regulatory fellow researchers at the TMC
expressed by our cells is tightly machinery underlying gene and beyond with the right
controlled and genetic variations expression variation in humans. expertise,” he says.
••••
12IMMPACT REPORT
Dr. Ashish Kapoor aims to better understand how disruptions in the regulation of gene expression lead to disease.
••••
13IMMPACT REPORT
Shavonnah Roberts Schreiber champions women’s health initiatives at the IMM.
••••
14Donor spotlight
A catalyst for change
P
ointing out a problem projects. A naturally inquisitive community awareness,” she
or a disparity is simple, person, she says she felt destined says. “Ultimately, I hope to raise
but taking the personal to become part of the IMM’s the endowment to an endowed
responsibility to address strong research environment, chair that will provide funding
it and develop a solution and it was not long before for an exceptional faculty
takes courage, leadership, she joined the IMM Advisory member to champion women’s
determination, and a healthy Council. health at the IMM.”
dash of creativity. Again, Roberts Schreiber As part of the endowment’s
As a business owner, asked herself what she could do outreach aim, Roberts Schreiber
volunteer leader, and more to bring positive change held an inaugural mixer on
philanthropist, Shavonnah and began further refining her March 8, 2018—International
Roberts Schreiber dedicates focus. Women’s Day—to engage
much of her life to solving “I narrowed it down to nearly 40 members of her own
problems she sees in everyday women’s health because it’s so network and inform them of
life and helping others find important to me,” she says. innovative women’s health
innovative solutions. “I’m always searching for ways initiatives at the IMM.
Her fascination with science to help women become strong, “I’m known in my network
and resolve to support women’s healthy, and whole human for being a connector of ideas
health initiatives blossomed into beings.” and people,” Roberts Schreiber
a natural partnership with The Although Roberts Schreiber says. “My goal is also to connect
Brown Foundation Institute says she felt that she was my network to UTHealth.
of Molecular Medicine for the productively contributing her Women’s health initiatives
Prevention of Human Diseases time and talents to the IMM, may not be each person’s
(IMM) at UTHealth. she felt she could have a greater philanthropic passion, but
“One thing I know to be philanthropic impact and began there’s so much happening here
true,” Roberts Schreiber says, “is seeking opportunities to provide that someone may find what
that there are gender disparities more support. they truly care about.”
in causes focused on women, “What really drove it home Two faculty members from
including health care. When for me was an IMM tour I the Center for Metabolic and
I dive into issues like this, I took,” she says. “I had the Degenerative Diseases at the
always ask myself, ‘What am I opportunity to learn how some IMM—Kristin Eckel Mahan,
going to do to become part of critical projects don’t get the Ph.D., assistant professor, and
the change I want to see?’” same level of funding from Rebecca Berdeaux, Ph.D.,
Roberts Schreiber was organizations and have to rely associate professor—shared their
a member of UTHealth on private donors.” innovative work and mingled
Luminaries, a volunteer The seed was planted, and with the group.
leadership group composed of she says she knew that an As Roberts Schreiber works
Houston’s young community endowment at the IMM could to empower women through
leaders, when she started feeling provide perpetual funding for her work and everyday life,
she could devote even more of women’s health initiatives— her endowment will help
her own talents and resources to thus, the Shavonnah Roberts bring critical funding and
benefit the university. Schreiber Women’s Health awareness to women’s health.
Seeking the perfect fit for Endowment was born. Through her philanthropy and
her passion at UTHealth, she “My vision is to support determination, she is setting
IMMPACT REPORT
attended an IMM Advisory physicians and researchers an example that she hopes will
Council meeting and quickly who directly impact women’s inspire others to become part of
became interested in the science health and to facilitate the positive change they want to
behind all of the innovative outreach events to spread see.
••••
15CENTER FOR CARDIOVASCULAR GENETICS
T
he IMM Center for Cardiovascular
Genetics, established in 2006,
focuses on elucidation of molecular
genetics, genomics, and pathogenesis of
cardiovascular diseases with the objective
of utilizing the discoveries to prevent and
treat cardiovascular diseases in humans. The
Center provides specialized clinical services
to patients with genetic cardiovascular
disorders at the Cardiovascular Genetic
Clinic. The Center also has a Research
Clinic, which is utilized for clinical research
activities, including NIH- and industry-
sponsored clinical trials.
Mission: To prevent and treat
cardiovascular diseases in humans through identification of new disease-causing genes and
identification and targeting of the pathogenic have advanced the genetic causes of heart failure.
genes and pathways. We are actively recruiting additional probands
Faculty: Priyatansh Gurha, Ph.D., assistant and family members.
professor; AJ Marian, M.D., professor; Raffaella II. Genomics studies of human heart failure
Lombardi, M.D., Ph.D., adjunct assistant and mouse models of cardiomyopathies: The
professor. studies predominantly relate to DCM and ACM
General theme of the research programs: The and included whole transcriptome analysis by
research programs at the Center start with human RNA-Seq, DNA methylation analysis by RRBS,
molecular genetic studies aimed at identifying and chromatin remodeling by ChIP-Seq of
the causal genes for human cardiovascular specific histones and proteins. The integrated
diseases. The focus is primarily on hereditary findings are used for preventive and theprautic
cardiomyopathies, which are important causes of targeting.
sudden cardiac death and heart failure. Genetic III. Therapeutic targeting of dysregulated
analysis is performed by whole exome and genome pathways in cardiomyopathies: Dysregulated
sequencing. Genetic discoveries are then coupled pathways identified through integrated genomics
with the genomic studies to identify differentially are targeted through genetic and pharmacological
expressed coding and non-coding transcripts and interventions in model organisms and their
dysregulated pathways, chromatin remodeling, effects on survival, cardiac function, and clinical
and DNA methylation in cardiomyopathies. The outcomes are analyzed. Several active programs
integrated approach is used to identify the key are current underway.
dysregulated pathogenic pathways for preventive IV. Clinical Studies: The Center participates
and therapeutic genetic and pharmacological in investigator-initiated, single-center pilot clinical
interventions. The findings in the model systems trials as well as industry-sponsored, multi-center
are extended to human patients through pilot clinical trials in hereditary cardiomyopathy.
randomized placebo-control double-blind studies An NIH-sponsored, double-blind randomized
clinical trials. The findings provide the platform pilot study (HALT-HCM) in patients with
for large-scale, multi-center efficacy clinical trials. HCM recently was completed. The Center also
Research Programs: participates in industry-sponsored clinical trials in
I. Human molecular genetic studies of cardiomyopathies.
cardiomyopathies: We have a repository of
several hundred cases and their family members AJ Marian, M.D.
with cardiomyopathies, including hypertrophic Center Director & Professor
cardiomyopathy (HCM), dilated cardiomyopathy James T. Willerson Distinguished
IMMPACT REPORT
(DCM), and arrhythmogenic cardiomyopathy Chair in Cardiovascular Research
(ACM). Pathogenic and causal variants are
identified by whole exome sequencing in the
probands and family members. These studies have
••••
16CENTER FOR CARDIOVASCULAR GENETICS
AJ Marian, M.D.
Professor and Director of the Center for Cardiovascular Genetics
James T. Willerson Distinguished Chair in Cardiovascular Research
Molecular genetics, genomics, pathogenesis, and treatment of
hereditary cardiomyopathies
is to link the causal mutations to genomic on improving symptoms and exercise toler-
remodeling and to the pathogenic pathways. ance in patients with obstructive hypertrophic
The responsible molecular mechanisms are cardiomyopathy
identified through molecular mechanistic stud-
ies in genetically modified animal models and KEY PUBLICATIONS
cultured cells. The mechanistic discoveries are Hypertrophy Regression with N-AcetyLcysTeine
then utilized to intervene in model organisms, in Hypertrophic CardioMyopathy (HALT-HCM): A
Our long-standing research objectives have utilizing genetic and pharmacological ap- Randomized Placebo Controlled Double Blind
been to delineate the molecular genetics, proaches that target the pathogenic pathways, Pilot Study, Marian AJ, Tan Y, Li L, Chang J, Syrris
genomics, and pathogenesis of hereditary in order to prevent the evolving phenotype and P, Hessabi M, Rahbar M, Willerson JT, Cheong
cardiomyopathies in humans and apply the reverse or attenuate the established phenotype. B, Liu C, Kleiman N, Bluemke D, Nagueh S. Circ
discoveries to prevent the evolving and reverse These findings in the model organisms are ex- Res. 2018; 122: 1109-1118 , PMID: 29540445
the established phenotypes of heart failure and tended to human studies through pilot random-
sudden cardiac death. We have active research ized placebo-controlled, double-blind clinical Suppression of Activated FOXO Transcription
programs in three common forms of hereditary trials. The findings, if favorable, are pursued Factors in the Heart Prolongs Survival in a
cardiomyopathies: through collaborative large-scale clinical trials. Mouse Model of Laminopathies., Auguste G,
Arrhythmogenic Cardiomyopathy (ACM): ACM Gurha P, Lombardi R, Coarfa C, Willerson JT,
is an enigmatic form of hereditary cardiomy- RESEARCH PROJECTS Marian AJ., Circ Res. 2018; 122: 678-692 ,
opathies that clinically presents with cardiac •Identification of causal genes for heart failure PMID: 29317431
arrhythmias, heart failure, and sudden cardiac and sudden cardiac death
death, particularly in the young. A unique •Identification and characterization of epigen- A Distinct Cellular Basis for Early Cardiac
feature of this disease is a gradual replacement etic and transcriptomic changes, including Arrhythmias, The Cardinal Manifestation of
of cardiac myocytes with fibro-adipocytes. There non-coding RNAs and histone modifications Arrhythmogenic Cardiomyopathy, and the Skin
is no effective therapy for ACM. in hereditary cardiomyopathies Phenotype of Cardiocutaneous Syndromes.
Hypertrophic Cardiomyopathy (HCM): HCM is •Identification and characterization of the Karmouch J, Zhou QQ, Miyake CY, Lombardi R,
the most common form of hereditary cardiomy- molecular pathways that link the genetic mu- Kretzschmar K, Bannier-Hélaouët M, Clevers H,
opathies, affecting ~ 1 in every 500 individuals tations to the clinical phenotype in patients Wehrens XH, Willerson JT, Marian AJ. Circ Res.
in the general population. The affected individu- with cardiomyopathies, including, delinea- 2017;121: 1346-1359. PMID: 29018034
als are typically asymptomatic and sudden tion of the mechanical signaling pathways
cardiac death is often the first manifestation of regulated at the intercalated discs LAB MEMBERS
this disease. HCM is the most common cause of •HALT-HCM (Hypertrophic Regression with Post-doctoral fellows: Gaelle Auguste, Ph.D.;
sudden cardiac death in the young. While there N-Acetylcysteine in Hypertrophic Cardio- Sirisha C Marreddy; Leila Rouhigharabaei, Ph.D.
are effective therapies to alleviate the patient’s myopathy) clinical trial (ClinicalTrial.Org Visiting scholars: Ping Yuan, Jinzhu Hu, M.D.
symptoms, there is no effective therapy to NCT01537926) Research associate: Grace Czernuszewicz, M.S.
prevent or reverse the disease process. •Maverick study: An industry–sponsored clinical Research and clinical nurse: Yanli Tan, RN
Dilated Cardiomyopathy (DCM): DCM is trial to test efficacy of an ATPase modulator
genetically the most heterogeneous form of
hereditary cardiomyopathies and a major cause
of heart failure and heart transplantation in the
young. The affected individuals often present
with symptoms of heart failure, cardiac arrhyth-
mias, and sometimes sudden cardiac death.
There are a number of effective pharmacologi-
cal and non-pharmacological therapies for DCM
but currently there is no cure for DCM.
The overall approach entails an integrated
approach that includes human molecular genet-
ic studies through high throughput whole exome
IMMPACT REPORT
and genome sequencing to identify the causal
genes and mutations, followed by genomic stud-
ies, including transcriptomics and epigenetics Differential CpG methylation in the
to define molecular remodeling of chromatin intergenic region human dilated
in the presence of causal mutations. The aim cardiomyopathy
••••
17CENTER FOR CARDIOVASCULAR GENETICS
Priyatansh Gurha, Ph.D.
Assistant Professor
Molecular mechanisms and functions of Non-coding RNAs and
epigenetic regulation in heart failure
regulator of gene dysregulation. KDM5 is a KEY PUBLICATIONS
histone demethylase that removes tri- and Gurha P 1*, Chen X*, Lombardi R, Willerson JT,
di-methylation of lysine 4 of histone H3 Marian AJ 1. Knockdown of Plakophilin 2 Down-
(H3K4me3), often leading to suppression of regulates miR-184 Through CpG Hypermeth-
gene expression. The role of KDM5 in heart and ylation and Suppression of the E2F1 Pathway
in laminopathies has not been documented so and Leads to Enhanced Adipogenesis In Vitro.
far. To determine the causal relation of KDM5 *Authors contributed equally Circ Res. 2016
The broad goal of my research is to better in laminopathies we re-expressed LmnaWT in Sep 2; 119(6):731-50. (Corresponding authors).
understand the role of gene regulatory mecha- Lmna-/-mouse (by AAV9) and found that this was
nisms involved in the pathogenesis of cardiomy- associated with rescue of the KDM5 network Auguste G, Gurha P, Lombardi R, Coarfa C, Willer-
opathies and heart failure. It is now clear that and decreased apoptosis and increased overall son JT, Marian AJ. Suppression of Activated FOXO
non-coding RNAs not only play a role in proper survival. Currently using a wide array of genomic Transcription Factors in the Heart Prolongs
heart function but also are involved in the approaches, and in vivo, RNAi approached we Survival in a Mouse Model of Laminopathies.
pathogenesis of cardiomyopathies and heart are investigating the tissue and cell type-spe- Circ Res. 2018 Mar 2; 122(5):678-692
failure. Previously, we identified a pathologi- cific contribution of KDM5 in laminopathies to
cal role of miR-22, one of the most abundant ascertain the elusive role of KDM5 in heart and LAB MEMBERS
miRNA in the heart. We demonstrated that miR- determine if induction of KDM5 is pathogenic in Research assistant: Jordi Coste Pradas
22 is a key regulator of cardiac hypertrophy and heart failure in general.
fibrosis. Building on these studies, our research
identified several dysregulated miRNAs in Ar- RESEARCH PROJECTS
rhythmogenic Cardiomyopathy (ACM), a primary •Role of lncRNAs in the pathogenesis of
disease of the myocardium that clinically mani- Cardiomyopathies
fests with cardiac arrhythmias, heart failure, • Identification and characterization of mo-
and sudden death. One of the key pathogenic lecular mechanisms and functions of Lysine
features of ACM is the gradual replacement of demethylase KDM5 in cardiomyopathies and
myocytes by fibro-adipocytes. Using genomic heart failure.
approaches along with LOF and GOF studies
we implicated miR-184 in the pathogenesis of
ACM. Specifically, we showed that miR-184 was
predominantly expressed in cardiac mesenchy-
mal progenitor cells, and in ACM an epigenetic
network encompassing E2F1 pathway and CpG
DNA methylation transcriptionally suppress
miR-184 expression in the heart. We showed
that suppression of miR-184 leads to enhanced
adipogenesis and overexpression of this miRNA
partially rescue the adipogenic phenotype in
ACM.
Recently, we have begun to investigate the
regulatory role of Lamin (LMNA) in reprogram-
ming the epigenetic code that governs gene
transcription ensuing cardiac phenotype in
Laminopathies. The objective of this study is to
identify and characterize molecular component
and mechanistic details that lead to tissue-
specific disease phenotypes in laminopathies.
By studying the human heart with an LMNA
mutation, an LMNA-deficient (Lmna-/-) mouse
IPA analysis of Upstream regulators that are upregulated (blue) and downregulated (red) in Lmna-/-
model, and isolated cardiac myocyte transcrip-
IMMPACT REPORT
hearts and there corresponding enrichment profile upon AAV9-LmnaWT treatment (FDRCENTER FOR HUMAN GENETICS
T
he Center for Human Genetics
works to generate new
understanding about genetic risk
for common cardiovascular diseases and to
use that information to identify effective
therapies for these diseases. High blood
pressure is an amplifying element that
drives cardiovascular disease risk from
stroke, heart, and kidney disease. These
diseases emerge in middle and later life and
so are interlinked with the normal processes
of aging. The genetic variation that makes
us unique individuals and that has been
passed to us from our parents impacts our
risk of these diseases. Our work targets the
identification of genes that contribute to
cardiovascular diseases and the mechanisms notable progress in the study of susceptibility
by which variation in these genes reshape the to stroke and age-related decline in cognitive
biological pathways in which disease emerges. function. A significant fraction of sudden cardiac
An emerging concept developing in our death results from rhythm disruptions that arise
laboratories is that an important element of in genetic variation in the proteins processing
chronic disease of the cardiovascular system is the electrical activity within the heart. Our
that these diseases involve a persistent state of newest faculty member, Dr. Ashish Kapoor, is an
inflammation. For example, in atherosclerosis, emerging leader in this field. We have shown that
the blood vessel wall is invaded by immune cells kidney injury associated with increased blood
and the danger posed in atherosclerotic plaques pressure results from the emergence of auto-
may reflect the ongoing level of inflammation in antibodies that damage tissues. This unexpected
them. We need a better understanding of these finding from Dr. Doris’ lab points to a role of
processes of “sterile inflammation” in which our immune system genetic variation in creating
immune systems become activated in response to disease risk. Dr. Ba-bie Teng continues to advance
the emergence of damage to our tissues. We need understanding of susceptibility to atherosclerosis
greater understanding of the genetic variants that and the interplay between new drug targets, such
determine whether these inflammatory responses as PSCK9, and lipoprotein uptake by cells. As our
subside or remain active or even advance. The understanding of the complexity of information
challenge of identifying these genetic variants is storage and retrieval in the genome expands,
made more complex by the fact that there is a our colleague Dr. Sidney Wang is addressing
lot of genetic variation affecting in our immune approaches to assess, extract, and exploit new
responses. In order to be able to adapt to the levels of genomic complexity that will inform
continuous and rapid mutation of pathogens like work in this field.
viruses and bacteria, our immune systems harbor All of us have had, or will have, one of our
extensive genetic variation. Such variation can close relationships in life disrupted by common
provide us a head-start in responding to new or cardiovascular disease. In the Center for Human
evolving pathogens. But it can also create risk Genetics we have the opportunity to work for
of disease later in life. As our living standards change, pushing forward the knowledge from
have increased and our lives have lengthened, the which current medicine draws towards new
advantages provided earlier in life can turn into insights and new opportunities for disease
threats to our health by increasing our risk of prevention.
chronic cardiovascular disease.
Progress in the laboratories of our investigators Peter A Doris, Ph.D.
IMMPACT REPORT
continues to yield exciting and important insights. Center Director & Professor
Our human population geneticists, working Mary Elizabeth Holdsworth Distinguished
under the direction of Dr. Myriam Fornage, University Chair in Metabolic and Inflammatory
are global leaders in their field, and are making Disease Research
••••
19CENTER FOR HUMAN GENETICS
Peter A. Doris, Ph.D.
Professor/Center Director
Mary Elizabeth Holdsworth Distinguished University Chair in Metabolic and Inflammatory
Disease Research
Genetics of cardiovascular end organ injury
is stressful for the bacteria, we are studying Dhande, I.S., S.M. Cranford, Y. Zhu, S.C.
whether there are strategies to place additional Kneedler, M.J. Hicks S.E. Wenderfer, M.C Braun,
stress on the gut bacteria that will limit their P. A. Doris. Susceptibility to hypertensive renal
capacity to enter the host and interact with host disease in the spontaneously hypertensive rat is
immune mechanisms. influenced by two loci affecting blood pressure
Antibody-mediated hypertensive renal and immunoglobulin repertoire. Hypertension
disease. We are using hypertensive animals 71(4):700-708, 2018.
High blood pressure is a common disease
that lack the ability to form antibodies to prove
and its impact on public health arises largely
the role of antibodies in disease pathogenesis. LAB MEMBERS
because it leads to secondary pathologies, for
We have applied a new protein-based array Post-doctoral fellow: Isha S Dhande, Ph.D.
example, stroke and progressive loss of kidney
technology to identify the targets that autoan- Research assistants: Yaming Zhu, M.D., Aniket
function. It is these “end organ” diseases that
tibodies bind to in order to create disease. We Joshi, B.S.
are the principal health cost of high blood pres-
are developing antibodies from cells cloned
sure. Risk of these diseases is not equal among
from animals with disease to discover if these
patients with high blood pressure as genetic
antibodies alone are sufficient to create
susceptibility to end-organ disease varies. For
disease.
example, risk of dialysis resulting from loss of
Genetic pathway of hypertensive renal
renal function in a hypertensive patient is best
disease. In this project we assess the role
predicted by whether relatives have experienced
of three genes that we have identified that
serious renal disease. Knowledge of the genes
carry variation that we have implicated in
that produce genetic susceptibility may indicate
disease pathogenesis. We are interested in how
the currently unknown path from high blood
these genes lead to altered antibody function.
pressure to end-organ damage. In turn, this may
Antibody formation is a random process that is
point to opportunities to prevent disease. We
honed to targets by interactions between T cells
have applied genetic and genomic methods to
and B cells that remove potentially harmful
study hypertensive end-organ disease. We have
antibodies that are self-reactive. Antibodies
discovered that disease results from genetic
that target bacterial proteins that resemble
variation that affects antibody function in the Hypertensive SHR-A3 rats experience renal
host proteins are refined by these T and B
system that we study. We have evidence that the injury, while similar SHR-B2 rats do not. We
cell interactions so that they can recognize
likely source of antigen stimulating this antigen discovered a single nucleotide mutation in the
their bacterial target without interrupting host
formation is the bacteria that live in the gut. gene Stim1 in SHR-A3. This causes a reduction
protein function. The three genes we are study-
They share a protein in common with mammals in the T regulatory lymphocytes which assist
ing are expressed in B cells, the unique cellular
that pathogenic antibodies target. This protein in specific antibody maturation. Replacing the
type that expresses and develops antibodies.
has an important protective function. Antibodies single erroneous nucleotide in Stim1 in SHR-A3
The repertoire of antibodies encoded by the ge-
may impede this function, leading to damage to restores T regulatory cell counts to those in
nome is highly variable among individuals, and
organs and the blood vessels supplying them. SHR-B2. B. The same mutation replacement
we are examining whether this can influence
the reactivities that antibodies develop. This also results in reduction in kidney damage
RESEARCH PROJECTS in SHR-A3 to the much lower levels seen in
requires applying novel genome sequencing and
Gut bacteria in induction of hyperten- SHR-B2.
assembly methods to acquire a full representa-
sive renal disease. High blood pressure
tion of the antibody-encoding genes.
appears to disturb the normal separation of
the gut bacteria from the host. We investigate
KEY PUBLICATIONS
whether hypertensive animals prone to renal
Dhande, I, Y. Zhu, M.C Braun, M.J. Hicks, S.E.
disease experience greater gut barrier dysfunc-
Wenderfer and P. A. Doris. Mycophenolate
tion than hypertensive animals resistant to
mofetil prevents cerebrovascular injury in
disease. We determine whether differences in
stroke-prone spontaneously hypertensive rats.
antibody genetics alters the gut bacteria and
Physiological Genomics 49:132-140, 2017.
constitutes another component of the defective
Doris, P.A. The genetics of hypertension: an
gut barrier. We are examining which bacteria
IMMPACT REPORT
assessment of progress in the spontane-
are successful in breaching the gut barrier and
ously hypertensive rat. Physiological Genomics,
whether passive or active immunization against
49(11):601-617, 2017.
these bacteria can modulate disease. Finally,
translocation of gut bacteria into the host
••••
20CENTER FOR HUMAN GENETICS
Myriam Fornage, Ph.D.
Professor
The Laurence and Johanna Favrot Distinguished Professorship in Cardiology
Molecular epidemiology of the aging brain
These discoveries may yield new insights into M. Genome-wide association study of 23,500
disease mechanisms and lead to the develop- individuals identifies 7 loci associated with
ment of new therapeutics to prevent or slow brain ventricular volume. Nat Commun. 2018;
disease progression. 9:3945.
RESEARCH PROJECTS Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-
•Discovering DNA sequence variants influenc- Nelson KL,et al., Schellenberg GD, Seshadri
Diseases of the aging brain, such as stroke ing ventricular enlargement on MRI, a key S, Naj AC, Fornage M, Farrer LA. Whole exome
and dementia, are among the most significant feature of several neurological and psychiatric sequencing study identifies novel rare and com-
public health problems of our time. Stroke is diseases mon Alzheimer’s-Associated variants involved in
the fifth-leading cause of death in the United •Discovering novel epigenetic (DNA methyla- immune response and transcriptional regula-
States and is a major cause of serious long- tion) variants that influence risk for brain tion. Mol Psychiatry. 2018 (in press)
term disability for adults. Alzheimer’s disease is small vessel disease and its related neuro-
now the sixth-leading cause of death and more cognitive outcomes Story Jovanova O, Nedeljkovic I, Spieler D,
than 5 million Americans are living with the •Discovering novel genetic variants for high Walker RM, Liu C, et al., Hou L, Eriksson JG, For-
disease. By 2050, this number is projected to blood pressure using gene-lifestyle interac- nage M, Deary IJ, Baccarelli A, Tiemeier H, Amin
reach 16 million. There is growing evidence that tions and pathway analysis. In particular, N. DNA Methylation Signatures of Depressive
these disorders begin years, if not over decades, discovering how depression and anxiety Symptoms in Middle-aged and Elderly Persons:
before manifestation of symptoms or clinical affects genetic risk of hypertension. Meta-analysis of Multiethnic Epigenome-wide
diagnosis. Indeed, neuroimaging techniques, •Investigating the distribution of the APOE4 Studies. JAMA Psychiatry; 75:949-959
such as magnetic resonance imaging (MRI), mutation, a major risk factor for cognitive
have consistently detected brain abnormalities decline and Alzheimer’s disease, in diverse LAB MEMBERS
beginning in middle age, which are associated Hispanics/Latinos Post-doctoral fellow: Xueqiu Jian, Ph.D.
with an increased risk of stroke, cognitive and Graduate students: Daokun Sun, M.D., M.P.H.;
functional impairment, dementia, and death. KEY PUBLICATIONS Yunju Yang, Ph.D.
We investigates the genetics and genomics of Vojinovic D, Adams HH, Jian X, Yang Q, Smith AV, Research assistants: Rui Xia, Ph.D., biostatisti-
vascular and neurodegenerative disease of the Bis JC, Teumer A, et al., Longstreth WT, van Duijn cian; Ping Wang, Ph.D., research associate
brain both in its clinical and pre-clinical forms CM, Launer LJ, Seshadri S, Ikram MA, Fornage
in large population samples from young adults
to elderly subjects.
We use powerful genome technologies to
discover novel genes influencing the risk for
stroke, Alzheimer’s disease, and brain MRI
abnormalities. In collaboration with research-
ers in the United States and Europe, we apply
genome sequencing technologies to identify
variants in the DNA sequence that influence
risk for these disorders. We also study the links
between DNA methylation and these diseases.
DNA methylation is an epigenetic mechanism
used by cells to control gene expression. Unlike
DNA sequence variants, DNA methylation marks
are not fixed at birth. Some of them can change
throughout the lifetime and in response to en-
vironmental influences and aging. For example,
we have used DNA methylation as a marker of
a person’s biological aging and compared it to
his/her chronological age. We have shown that
individuals whose biological age estimated from
IMMPACT REPORT
their DNA methylation profile is significantly
older than their chronological age are at in-
creased risk of developing brain abnormalities Investigating the genome for genetic variations that influence Alzheimer’s disease and its neuroimag-
and cognitive function impairment. ing features provides new clues for unraveling disease mechanisms.
••••
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