The goal of the Translational Medicine Program is to harness the rich clinical cardiovascular population at the Massachusetts General Hospital to identify and validate novel genomic determinants of cardiovascular disease. Our goal is not to capture the entire cohort of cardiovascular patients presenting to Massachusetts General Hospital, but rather to focus our efforts on extremely well-phenotyped human models that are unique to cardiovascular disease. Of particular interest are "perturbational" studies in humans (e.g., cardiac exercise testing) that elicit robust phenotypes in affected individuals to serve as the springboard for analyses that span from genomics to proteomics and biochemical profiling. The Translational Medicine Program will involve a multidisciplinary group of investigators who contribute expertise in cardiovascular basic science, clinical cardiology, genetic/genomic epidemiology, bioinformatics, imaging, pathology, as well as clinical chemistry and mass spectrometry. While the Program in Translational Medicine will be physically located at the Massachusetts General Hospital Main Campus, the effort will leverage ongoing interdisciplinary collaborations with investigators at the Framingham Heart Study, the Broad Institute of M.I.T., Harvard University, and Harvard Medical School. Our goals are to:
• Identify specific unmet needs in cardiovascular biomarker and pathway discovery
(e.g., genomic markers of subclinical premature coronary artery disease, serum
biomarkers of myocardial ischemia)
• Match cutting-edge technologies with our unique patient cohorts for “first in man” studies
• Establish the infrastructure necessary to phenotype patients with the targeted condition
(from plasma samples, RNA, DNA, imaging, etc.) and enroll sufficiently sized cohort(s)
with the requisite power to validate novel biomarkers.
• Establish scientifically high priority research projects to target for independent funding.
• Ultimately, develop novel therapeutic interventions.
While efforts in translational investigation are already underway, this program will identify synergies between ongoing studies and catalyze new opportunities. Several of the ongoing projects that are anticipated to serve as cornerstones of this effort include:
Proteomics and Metabolomics Studies (PI: Gerszten , Wang)
Recent advances in proteomic and metabolic profiling technologies have enhanced the feasibility of high throughput patient screening for the diagnosis of disease states. Small biochemicals and proteins are the end result of the entire chain of regulatory changes that occur in response to physiological stressors, disease processes, or drug therapy. In addition to serving as biomarkers, both circulating metabolites and proteins participate as regulatory signals, such as in the control of blood pressure. Our ongoing studies have helped pioneer the application of novel mass spectrometry and liquid chromatography techniques to plasma analysis. In parallel with the profiling efforts, we have developed statistical software for functional pathway trend analysis and used it to demonstrate significant coordinate changes in specific pathways. Such analysis allows us to gain insight into the functionally relevant cellular mechanisms contributing to disease pathways and increases the likelihood that prospective biomarkers will be validated in other patient cohorts. Support for this effort would be synergistic with ongoing funding, including the recent appointment and support for Dr. Gerszten to lead a metabolomics initiative at the Broad Institute.
Cardiovascular Genetics and Genomics Studies (PIs: Kathiresan, Newton-Cheh, Wang, and O'Donnell)
Through the Human Genome Project and the International Haplotype Map project, researchers now have available the complete human genome sequence, a nearly complete set of common single nucleotide polymorphisms (SNPs), and a map of the patterns of correlation ("linkage disequilibrium") among SNPs. Research on a large-scale is now possible to define associations of common, complex human cardiovascular diseases —such as myocardial infarction and sudden cardiac death—with genetic variants using candidate gene and genome-wide association studies, gene sequencing, and family-based linkage studies. Specific diseases and traits being studied by CVRC researchers include early-onset myocardial infarction, sudden cardiac death, blood lipids, blood pressure, electrocardiographic QT interval and blood hemostatic factor levels. These studies draw clinical material from the Massachusetts General Hospital and from collaborations with population-based epidemiologic cohorts such as the Framingham Heart Study. Like the metabolomics/proteomics work, these efforts build on the technologic and scientific expertise at the Broad Institute. Specifically, CVRC researchers leverage the Broad Institute’s expertise in large-scale genotyping, genomics, and statistical genetics. The collaboration between the Massachusetts General Hospital, the Framingham Heart Study, and the Broad Institute brings together resources that are unique to each institution to identify genes related to complex cardiovascular traits and to ultimately impact human health.
Chemical Biology Program (PIs: Peterson and Shaw)
Dr. Peterson's group has championed the zebrafish as a tool for drug discovery. The zebrafish has become a widely used model organism because of its fecundity, its morphological and physiological similarity to mammals, the existence of many genomic tools and the ease with which large, phenotype-based screens can be performed. Because of these attributes, the zebrafish also provides opportunities to accelerate the process of drug discovery. By combining the scale and throughput of in vitro screens with the physiological complexity of animal studies, the zebrafish promises to contribute to several aspects of the drug development process, including target identification, disease modeling, lead discovery and toxicology. The Program in Translational Medicine will specifically support efforts to test novel pro-angiogenic factors (discovered as suppressors of the "gridlock" phenotype in zebrafish) on human cells such as circulating endothelial precursors.
Dr. Shaw's group is studying the cellular effects of human disease mutations in patient samples, by perturbing cells with a panel of thousands of drugs, and asking whether mutant versus wild-type cells react differently to a given biochemical (reminiscent of a genetic interaction screen). Dr. Shaw has demonstrated the feasibility of this approach using lymphoblast cell lines from a family affected by a monogenic form of diabetes (MODY1), and shown that glucocorticoid signaling differs between affected vs. unaffected patients. Because his studies incorporate the use of FDA-approved drugs, he can quickly identify both potentially "druggable" disease pathways as well as novel therapeutic agents. Further validation of these efforts in other monogenic disorders, such as LDL-receptor deficient patients is planned next. Ultimately this work will be extended to studies in complex genetic diseases.
Director: Rob Gerszten, MD
• Farouc Jaffer, MD, PhD
• Sekar Kathiresan, MD
• Chris Newton-Cheh, MD, MPH
• Randall Peterson, PhD
• Stanley Shaw, MD, PhD
• Thomas Wang, MD