Clonal hematopoiesis as a mediator of cardiovascular disease in women with premature menopause

项目摘要/摘要

PROJECT SUMMARY / ABSTRACT This NIH Mentored Clinical Scientist Research Career Development Award (K08) proposal describes a five- year training program for mentored career development in academic cardiovascular medicine. The principal investigator, Dr. Michael Honigberg, is a staff cardiologist at Massachusetts General Hospital (MGH), an Instructor of Medicine at Harvard Medical School, and a prior trainee of the NHLBI-sponsored T32 training grant at Brigham and Women’s Hospital. The primary goal of this award is for the candidate to obtain the training and skills necessary to become a successful independent physician-scientist. His long-term career goal is to use multi-omics approaches to elucidate disease mechanisms and discover novel targets for the prevention and treatment of heart disease, with a focus on cardiovascular disease (CVD) in women. Clonal hematopoiesis of indeterminate potential (CHIP) refers to the expansion of blood stem cells harboring acquired mutations in leukemia-associated genes. CHIP predisposes to accelerated atherosclerosis. In Dr. Honigberg’s preliminary work, he showed that women with a history of premature menopause are enriched for CHIP by 1.4-fold and that CHIP is independently associated with incident CVD in postmenopausal women. He now proposes to test the hypothesis that CHIP is a key mediator of accelerated CVD in women with premature age of menopause using multiple complementary approaches. In Aim 1, he will associate age at menopause with expansion of CHIP clones over time and incident CVD in cohorts with serial next-generation sequencing. In Aim 2, he will use large proteomic datasets to discover and validate novel protein biomarkers of CHIP and test the role of these proteins in premature menopause-associated CVD. In Aim 3, he will use machine learning approaches to train, validate, and test a CHIP risk classifier to guide CHIP screening in women. The proposed training plan involves primary mentorship from Dr. Pradeep Natarajan, an expert in genomics and atherosclerotic CVD prevention, and co-mentorship from Dr. JoAnn Manson, principal investigator of the Women’s Health Initiative and an expert in menopause, sex hormones, and CVD in women. Both mentors are enthusiastic about supporting Dr. Honigberg’s career development. The training plan additionally involves a distinguished Scientific Advisory Committee including experts in proteomics and multi-omics investigation (Dr. Robert Gerszten, Beth Israel Deaconess Medical Center), clonal hematopoiesis and myeloid malignancy (Dr. Benjamin Ebert, Dana-Farber Cancer Institute), inflammation and vascular biology (Dr. Peter Libby, Brigham and Women’s Hospital), and machine learning (Dr. Puneet Batra, Broad Institute of MIT and Harvard). The candidate will leverage coursework, facilities, and resources from across MGH, Harvard University, MIT, and the Broad Institute toward completion of his proposed training and research plan. Dr. Honigberg’s structured training plan will develop the skills necessary to pursue a research program distinct from that of his mentors and will facilitate his transition to an independent, R01-funded physician-scientist.