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

项目总结/摘要 NIH指导临床科学家研究职业发展奖（K08）提案描述了一个五- 一年的培训计划，指导学术心血管医学的职业发展。校长 研究者Michael Honigberg博士是马萨诸塞州总医院（MGH）的心脏病专家， 哈佛医学院医学讲师，以及NHLBI赞助的T32培训的先前受训者 布里格姆妇女医院的补助金该奖项的主要目标是让候选人获得 培训和必要的技能，成为一个成功的独立的医生，科学家。他的长期职业生涯 目标是使用多组学方法来阐明疾病机制，并发现新的靶点， 预防和治疗心脏病，重点是妇女的心血管疾病。 不确定潜能的克隆性造血（CHIP）是指具有不确定潜能的造血干细胞的扩增。 获得性白血病相关基因突变CHIP易于加速动脉粥样硬化。博士米切尔 Honigberg的初步工作表明，有过早绝经史的妇女， CHIP增加1.4倍，CHIP与绝经后妇女CVD事件独立相关。他 现在提出测试的假设，CHIP是一个关键的调解人加速心血管疾病的妇女过早 更年期使用多种互补的方法。在目标1中，他将年龄与绝经期联系起来， 随着时间的推移CHIP克隆的扩增和连续下一代测序队列中的CVD事件。 在目标2中，他将使用大型蛋白质组学数据集来发现和验证CHIP的新型蛋白质生物标志物， 测试这些蛋白质在过早绝经相关CVD中的作用。在目标3中，他将使用机器 学习方法来训练，验证和测试CHIP风险分类器，以指导女性CHIP筛查。 拟议的培训计划包括基因组学专家Pradeep Natarajan博士的主要指导 和动脉粥样硬化性心血管疾病的预防，并共同指导博士乔安曼森，首席研究员的 妇女健康倡议和专家在更年期，性激素和心血管疾病的妇女。两位导师都是 热心支持霍尼伯格博士的职业发展。培训计划还包括 杰出的科学咨询委员会，包括蛋白质组学和多组学研究专家（博士。 罗伯特Gerszten，贝斯以色列女执事医疗中心），克隆造血和骨髓恶性肿瘤（博士。 Benjamin Ebert，Dana-Farber癌症研究所），炎症和血管生物学（Peter Libby博士，Brigham 和妇女医院），以及机器学习（Puneet Batra博士，麻省理工学院和哈佛的布罗德研究所）。的 候选人将利用来自MGH，哈佛大学，麻省理工学院和 布罗德研究所完成了他提出的培训和研究计划。霍尼格伯格博士 培训计划将发展必要的技能，以追求一个不同于他的导师的研究计划 并将促进他过渡到一个独立的，R01资助的医生科学家。

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.