Interdisciplinary Training in Genetics and Complex Diseases Roadmap Grant
The Interdisciplinary Training in Genetics and Complex Diseases Roadmap grant was funded by the NIDDK and ran from 09/30/04 – 07/31/09. The primary focus of the training grant was to develop a cadre of young scientists who can participate at the intersection of molecular biology, epidemiology, and biostatistics to become leaders in integrative and team approaches to understanding genetics and complex diseases in the public health arena. Aims were: 1) to establish a new track for interdisciplinary education that intersects the boundaries of molecular biology, epidemiology and biostatistics with a core foundation in cell physiology and metabolism that will develop key concepts focused on context-dependent gene-environment interactions in complex diseases; and 2) to develop integrated coursework, sponsor workshops, establish a new seminar series, and foster interactive “cores” to enable our trainees to undertake the challenges that lie ahead to define the molecular signatures of disease patterns.
Former Roadmap Fellows
Haiming Cao, Ph.D.
Erin Johnson, Ph.D.
Kihwa Kang, Ph.D.
David Kim, Ph.D.
Yelena Margolin, PhD
Clifford Meyer, Ph.D.
Jeremy Stuart, D.Sc.
Weidong Tian, Ph.D.
Kelvin Tsai, M.D.
Hongying Zhong, Ph.D.
Elena Austin is a student in the DS program in Environmental Health, supervised by Dr. Petros Koutrakis. Elena has played violin since the age of 4, and has a graduate degree in violin performance in one of the top-ranked US music conservatories (Mannes College of Music). Her formal training in music was simultaneously paralleled with studies in science and math, and she graduated with a joint major in mathematics and physiology from McGill University. She has been active in NIOSH-funded research in the laboratory of Beverly Cohen and Judy Xiong at NYU, and has been drawn to the emerging field of nanotechnology. Her goal is to study dosimetry patterns of nanostructural particles and their movement through biological systems following exposure. She is affiliated with the Aerosol Technology Laboratory at HSPH, supervised by Dr. Petros Koutrakis.
Rajeev Ayyagari is a predoctoral student in the Department of Biostatistics. He has a unique background in both biostatistics (BSc and MS degrees at Indian Statistical Institute) and computer science (MS degree from University of Maryland). His efforts have been largely focused on computational aspects of statistics (data mining and statistical learning theory) and during his MS degree, he designed efficient algorithms for data mining problems and computationally intensive statistical applications. Recognizing that he wished to pursue research in an academic setting, he applied to our program with the “desire to be at the center of progress in this interdisciplinary effort, rather than contribute from the edges.”
Prerna Bhargava is a predoctoral student in the Biological Sciences in Public Health (BPH) program. She graduated from Brandeis University with a B.S., where she studied genetic instability. Her studies at Brandeis also involved legal issues as a minor, so she has past interdisciplinary training in her “passion for biochemical research, patient advocacy, and the law”. Prerna is currently performing her thesis research in the area of lipid metabolism and inflammation in Dr. Chih-Hao Lee’s laboratory.
Matthew Blahna is a HSPH predoctoral student in the Biological Sciences in Public Health (BPH) program. Matt has a BS and MPH degrees from the University of Michigan. His efforts have been largely focused on population dynamics responsible for the emergence of antimicrobial resistant pathogens. His previous thesis work in the MPH program at UMichigan examined the dissemination of virulence factors and antibiotic resistance genes among uropathogenic E. coli and he is first author of a paper reporting the distribution of trmethoprim-sulfamethoxazole resistance genes among uropathogens in Europe and Canada. He also is coauthor on a paper examining the population dynamics of a newly proposed uropathogenic E coli clonal group and he is finishing work with researchers at the Center for Molecular and Clinical Epidemiology of Infectious Disease to utilize microarray technology for gene discovery in pathogenic and commensul E coli. Recognizing that his “goals require a mulit-disciplinary and inter-departmental education” he applied to our to obtain basic biological research training since his goals “require the utilization of molecular biology laboratory techniques, epidemiological surveys and nonlinear systems models”.
Haiming Cao, Ph.D. (Biochemistry, University of Nevada-Reno): Postdoctoral fellow co-mentored by Drs. Gokhan Hotamisligil and Alexander Ivanov at Harvard School of Public Health. Fatty acid binding proteins play critical roles in inflammatory and metabolic responses. Using gene expression profiling, Haiming is studying mouse models deleted in the fatty acid binding protein aP2 and mal1 to characterize the effects of diet induced obesity on adipocyte gene expression. He will also collaborate with the HSPH proteomics core, under the supervision of Dr. Ivanov, to identify protein interactions and potential post-translational modification of fatty acid binding proteins. These studies will eventually be extended to use ‘lipidomics’ in order to characterize the content of lipid bodies and how these organelles are regulated by fatty acid binding proteins. Haiming’s project combines state-of-the-art high throughput analytical techniques to address outstanding questions about metabolic syndrome.
Lana Dinic is a HSPH predoctoral student in the Biological Sciences in Public Health (BPH) program. Lana has a BS degree in Life Sciences from Mt. Holyoke College. She applied to our program “motivated by a passion for making meaningful contributions to knowledge that will address problems in human disease”. In particular, her interests lie in reducing the impact of infectious disease on global health, and she is seeking to develop expertise in the area of molecular biology of pathogenic organisms.
Meric Erikci is a PhD student in the Biological Sciences in Public Health program at HSPH. She is a recent graduate from Bilkent University (Turkey), where she was the first-ranked student in the Department of Molecular Biology and Genetics. Meric has a wide variety of previous laboratory experience, from bioinformatics and analysis of chip-array data (Tayfun Ozcelik, Bilkent University) to studies of metabolic stress and inflammation (Fahri Saatcioglu, University of Oslo). Her interests are to study “the underlying mechanisms in diseases through analyzing interactions between environmental input and molecular responses tin an interdisciplinary context.”
David Fardo: Predoctoral student, PhD candidate in the Department of Biostatistics. David examined the effects of differing phenotype characterizations on the power to detect a disease susceptibility locus / phenotype association. Specifically, his project used R-based simulations of trios (simulated genotype and phenotype of one offspring and genotypes of both parents) to compare the power of family based association tests (FBATs) when using a continuous trait against different rules of dichotomizing the trait. These simulations were carried out using a progression of reasonable assumptions regarding heritability, allele frequency and sample size in order to gauge how the different dichotomizations affect power in varying situations.
Meg Gustafson Gregor: HSPH predoctoral student in the BPH program. Meg has begun to study the role of Stamp 1 and 2 proteins in cellular metabolism. Stamp2, a six-transmembrane protein with oxido-reductase capabilities, has been shown to be necessary for proper insulin signaling in adipose tissue. However, little is known about its mechanism of action. Stamp1 is a highly homologous family member with a different tissue profile, predominantly expressed in the brain and prostate, and present at lower levels in the kidney, spleen, and white adipose tissue. Its function is as yet unidentified. Cell culture and mouse models are the primary tools used to investigate the metabolic functions of the Stamp molecules and their importance in maintaining appropriate insulin signaling.
Jessie Hsu: Predoctoral student in the Department of Biostatistics. She has combined training with a BS degree from the University of Washington as a double major in biochemistry and statistics. Her research experience as a Howard Hughes Medical Institute Research Intern at the Fred Hutchinson Cancer Research Center in Seattle was her inspiration for pursuing a PhD in biostatistics. She studied nucleotide diversity in human olfactory genes with an aim to quantify genetic variation and to describe selective pressures underlying allelic diversity. This background in computational biology fit well with the training the Roadmap program seeks to provide. Jesse’s ultimate goal is to be a “biostatistician at a research institution …[to] engage in collaborative research with scientists and doctors.”
Erin Johnson, Ph.D. (Medical Sciences, Medical College of Ohio): Post-doctoral fellow co-mentored by Drs. Marianne Wessling-Resnick and Megan Murray. Erin’s project is to investigate the relationship between reticuloendothelial iron status (specifically regulated by the iron export protein, ferroportin) and intracellular Mycobacterium tuberculosis (M.tb) growth and infection. Conducting experiments with a pathogen such as M.tb requires extensive BL3 level training. Erin is in the process of finishing this training and will be able to operate independently following completion of the final skills test. While training, Erin also conducted several experiments with the BL2 level Mycobacterium bovis-BCG aimed at discerning a role for ferroportin in modulating intracellular mycobacterial growth. These preliminary experiments helped to develop a novel immunofluorescence-based approach for quantifying intracellular bacteria using scanning cell microscopy. The results suggest that ferroportin is a negative regulator of intracellular mycobacterial growth. Erin was also a co-author on a paper exploring a similar role for ferroportin in regulating the growth of Salmonella, another obligate intracellular pathogen. In addition to performing bench work, Erin is also participates in weekly group meetings held by Dr. Murray. These meetings are conducted to discuss and coordinate active tuberculosis epidemiology studies being carried out in both South Africa and Peru. An ultimate goal is to translate findings on disease progression and human genetic variation into a model system for cell culture studies.
Kihwa Kang, Ph.D. (Food Microbiology and Toxicology, University of Wisconsin-Madison): Postdoctoral fellow co-mentored by Drs. Chih-Hao Lee and Frank Hu at Harvard School of Public Health. Hypertriglyceridemia is frequently associated with obesity and metabolic diseases including insulin resistance. Based on the findings that nuclear receptor PPAR delta senses dietary lipids and regulates fat catabolism, the hypothesis behind Kihwa’s project is that PPARd is a key regulator of metabolic homeostasis and insulin sensitivity. Her project examines the effect of receptor deletion on glucose and lipid metabolism as well as on insulin signaling using mouse models. As nuclear receptors control biological processes through transcriptional regulation, she seeks to identify target genes of PPAR in critical metabolic pathways to dissect the molecular mechanism by which PPAR regulates metabolism. After establishing the role of PPAR in metabolic homeostasis and insulin sensitivity, she will test gene-diet interactions by examining whether PPAR delta polymorphisms modify the effects of dietary fatty acids and carbohydrates on risk of developing obesity, the metabolic syndrome, and type 2 diabetes. A large cohort study led by Dr. Frank Hu lends itself to this interdisciplinary investigation.
Jun Kawasaki is a HSPH predoctoral student in the Biological Sciences in Public Health (BPH) program. Jun has a BA in Biology from Grinnell College and enters our program with a keen interest in cancer research. She seeks to pursue questions about signal transduction pathways critical for tumor development from both cellular and clinical aspects, using genetic and molecular approaches. Her undergraduate research studies focused on nutritional products that have chemopreventive and chemotherapeutic effects, and her findings were recently presented at the Experimental Biology 2006 meeting, which she was invited to attend last April. Jun’s broad interests fit in well with the interdisciplinary nature of our program.
David Kim, PhD (Environmental Sciences and Engineering, The University of North Carolina at Chapel Hill): Postdoctoral fellow co-mentored by Drs. Thomas Smith (Harvard School of Public Health) and Guido Guidotti (Harvard College). In the last decade, a number of important discoveries have been made regarding the role of membrane proteins (i.e., transporters). Transporters are expressed at higher concentrations in the epithelium of the stomach, intestines, kidneys, liver, and brain. They can restrict the access of many compounds to the central nervous systems, decrease the bioavailability of drugs, and limit the transport of teratogens to the fetus. Despite the overall significance of transporters, their role in determining the pharmacokinetic behavior of environmental toxicants is poorly understood. The objectives of David’s study are (1) to identify environmental toxicants that can potentially interact with transporters, and (2) to examine the relative importance of transporters for the bioavailability of environmental toxicants. The hypothesis behind David’s project is that transporters will decrease the toxicity of environmental contaminants by restricting uptake into the systemic circulation and increasing clearance. David will implement computational tools to examine the structural and functional properties of chemicals that interact with transporters. He will use the results from this analysis to develop quantitative structure-activity relationship (QSAR) models that are predictive of pharmacokinetic parameters, such as the maximum efflux rate. David will also develop a quantitative description (i.e., physiologically-based pharmacokinetic model) of the interaction between chemicals and transporters, and use this description to predict the bioavailability of chemicals. The results of David’s project will contribute to a better understanding of and ability to predict individual risks from exposures to environmental toxicants.
Alvin Ling received the BSc degree in biochemistry from McGill University last spring. Alvin was selected for our program because he seeks to combine ‘various aspects of nutrition, epidemiology and genetics’ in his research. He is seeking “the opportunity to collaborate with scientists from an even wider range of disciplines to solve biological questions from a variety of different perspectives.”
Jessica Lucas is a predoctoral student in the Biological Sciences in Public Health (BPH) program. She graduated from Princeton University. As an undergraduate, Jessica was able to “integrate my interest in understanding cancer’s complex genetic and environmental causes with my fascination for policy issues related to pharmacogenomics, including implications of genetic screening, the development of tailored therapeutics, and the potential for biomarker-based prevention and clinical management of disease [by] pursuing a certificate in public policy at the Woodrow Wilson School of Public and International Affairs.” This broad translational experience was complemented by research internships at Wyeth’s Oncology Department each summer of her undergraduate career.
Yelena Margolin, Ph.D. is a Postdoctoral Research Fellow supervised by Drs. Alexander Ivanov, Xihong Lin, and Gokhan Hotamisligil. Oxidative stress is a prominent feature of a great variety of diseases, such as arthrosclerosis, cancer and diabetes. Identification of basic molecular mechanisms involved in cellular response to oxidative stress is needed for understanding of the pathogenesis of these diseases. Yelena’s project involves the use of proteomics to characterize the evolution of cellular oxidative stress response in a comprehensive, consistent, and time-resolved manner, as well as the development of analytical and statistical tools that can be used in the future studies of other basic molecular processes. An in vitro experimental model of oxidative stress, in which cultured mammalian cells are treated with different concentrations of hydrogen peroxide, is used in all experiments. Proteomic state of these cells is assessed after subcellular fractionation, followed by protein isolation and characterization by nano-liquid chromatography and tandem mass spectrometry (nano-LC/MS/MS). Enrichment procedures are applied to the subcellular fractions, resulting in selective isolation of proteins containing post-translational modifications, such as phosphorylation, glycosylation, acetylation and ubiquitination, that are subsequently characterized by nano-LC/MS/MS. Yelena is working with Xihong Lin, a bioinformatics specialist, to develop in-house computational and statistical platforms to yield a list of quantitative and qualitative changes in a) composition of the proteome and b) levels of proteins’ post-translational modifications, as a function of time, subcellular localization and concentration of hydrogen peroxide.
Clifford Meyer, Ph.D. (Chemical Engineering, Princeton University): Postdoctoral fellow co-mentored by Drs. Shirley Liu and Myles Brown at DFCI. Their joint research project was on chromatin immunoprecipitation (ChIP) tiling arrays and the development of analysis software that is reliable, easy-to-use and capable of representing important features of the data and their relation to the genome. Cliff’s particular interests reside in normalization of raw data, data filtering, ChIP-enriched region location and the identification of binding sites and features of the genome such as protein coding sequences and motifs.
Natalie Moroz is a predoctoral student in the Biological Sciences in Public Health (BPH) program. She recently completed her undergraduate degree at Brown University. She has extensive research experience in a variety of fields, having worked on projects in alcohol and behavior (Klaus Miczek, Tufts University), Parkinson’s Disease (Michael Scholssmacher, Harvard Medical School), and chronic obesity (Suzanne de la Monte, Brown University). She was selected for the roadmap training program because of her vision “to utilize an integrated neuroscience approach to study how impaired brain function leads to the development of insulin resistance and type 2 diabetes”.
Edward Ruiz-Navaerez: HSPH predoctoral student, and DSc candidate in the Departments of Epidemiology and Nutrition. Apolipoprotein CIII (apoCIII) and AV (apoAV) regulate triglyceride metabolism in opposite ways. Also, several studies have shown that naturally occurring sequence variation in both APOC3 and APOA5 genes affects plasma triglyceride levels, but evidence for an association with risk of coronary heart disease (CHD) is scarce. Edward’s work involved analysis of single nucleotide polymorphisms (SNPs) in the APOC3 and APOA5 genes to determine whether haplotypes defined by these genetic variants are associated with the risk of nonfatal myocardial infarction (MI) in the Costa Rican population. He also examined whether haplotypes interact with non-genetic factors (for example, diet) on the determination of MI risk or plasma lipid concentrations.
Kristopher Stanya, Ph.D.is a postdoctoral research fellow in the Department of Genetics and Complex Diseases mentored by Dr. Chih-Hao Lee. Nuclear receptors (NRs) play an important role in many biological processes, including development, reproduction and metabolic homeostasis. Dr. Stanya is examining the role of SMRT, a nuclear receptor co-repressor, in metabolism, inflammation and aging. SMRT modulates NR activity through the recruitment of a repression complex. Kris will study a new mouse model carrying knock in mutations in SMRT, that abolish its interaction with NRs. Preliminary data suggest that SMRT mutant mice exhibit increased differentiation potential of several progenitor cells, including pre-adipocytes and bone marrow. These studies will elucidate molecular mechanisms through which NRs and SMRT control cell fate determination of pre-adipocytes and hematopoietic stem cells.
Jeremy Stuart, D.Sc. (Cancer Cell Biology, Harvard School of Public Health): Post-doctoral fellow co-mentored by Drs. Zhi-min Yuan and Gokhan Hotamisligil. One of the most over-looked aspects of obesity-associated disorders is the predisposition to tumors. Jeremy tested the hypothesis that adipose tissue produces factors that modulate the growth of tumor cells and contribute to the cancer risk associated with weight gain. To address this question, he studied the interaction between adipocytes and tumor cells in vitro using a 3D cell culture approach. The ultimate goal being to identify adipocyte derived factors regulating tumor growth in vitro.
Weidong Tian, Ph.D. (Bioinformatics, Washington University): Postdoctoral fellow co-mentored by Drs. Fritz Roth and Heather Nelson. Weidong’s project took advantage of the fact that non-melanoma skin cancer, which is the most frequently diagnosed malignancy in humans, can serve as a model for understanding genetic susceptibility to cancer. Working with Dr. Fritz Roth, Weidong plans to develop a principled candidate gene approach applying a fully integrated probabilistic model for predicting genes potentially involved in skin cancer development. His work in this area will greatly benefit from the co-mentorship of Dr. Heather Nelson, who has strong expertise in epidemiology and the biology of skin cancer. She has developed a large population-based case control study of skin cancer in New Hampshire, and with access to DNA from this population, Weidong can directly test the association between variants in candidate genes and case status in Dr. Nelson’s epidemiologic study. Variation in genes that modify UV exposure, as well as those involved in DNA damage response and repair are known to affect individual susceptibility to skin cancer, thus we viewed this particular research project to be in keeping with our training goal for interdisciplinary research in molecular biology, epidemiology, and biostatistics in a team-oriented environment with the prospect of developing a novel candidate gene approach to mapping complex traits.
Kelvin Tsai, M.D.: HSPH graduate of the BPH program. Kelvin employed heterotypic coculture models to study the interactions between mammary stromal fibroblasts and epithelial cells. This model system explores the effects of low-level stress and cell premature senescence on breast morphogenesis and carcinogenesis. His work led to a first author paper published in Cancer Research.
Sara Vallerie: HSPH predoctoral student, BPH program. Sara’s projects focused on elucidating the roles of JNK1 and JNK3 in the metabolic syndrome. JNK1 and JNK2 have already been shown to be key players in obesity-associated disease. Using molecular and cellular biology, physiological, and biochemical techniques, Sara explored their roles in metabolic disease. Sara was recently awarded an individual NRSA to support her efforts.
Katy Wellen: HSPH graduate of the BPH program. Katy’s project focused on understanding the metabolic role of a poorly understood protein called Stamp2. Found primarily in adipocytes and regulated by both nutritional and inflammatory stimuli, this protein may represent a point of intersection for metabolic and inflammatory pathways. Katy used both cell culture and mouse models to investigate the role of Stamp2 in adipocyte function and whole body energy metabolism. She has several manuscripts pending publication from her studies.
Li Ye is a HSPH predoctoral student in the Biological Sciences in Public Health (BPH) program. He graduated from Tsinghua University with a BS degree in Biological Sciences this June. He has twice received a First Prize Scholarship for academic excellence from Tsinghua University, and was a Gold Medal winner in the National Biology Olympiad of China in 2002. He is seeking to apply his talents to systems biology, and in his statement he indicated that he was attracted to our program because of its “integrated multidisciplinary approaches÷.not only [have we] covered essential issues such as genetic basis, stress responses and metabolic regulation of diseases, but also investigated them at the mechanism level as well as in the context of population studies”.
Hongying Zhong, Ph.D. (Chemistry, University of Alberta): Postdoctoral fellow associated with Proteomics Core in a joint research project led by Drs. Dieter Wolf, Alexander Ivanov, Gokhan Hotamisligil, Frank Sacks, Louise Ryan and Eric Rimm. This combined research effort focused on identifying biomarkers for metabolic disease, including diabetes and coronary heart disease, using plasma proteomics. Hongying’s role in this team-directed effort was to devise standardized plasma sample preparation affording sensitivity, reproducibility and throughput. Mouse models of metabolic disease were used to develop and test this technology.