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

项目摘要/摘要 这份NIH指导的临床科学家研究职业发展奖(K08)提案描述了五个- 学术心血管医学指导职业发展的一年培训计划。校长 研究员迈克尔·霍尼格伯格博士是马萨诸塞州综合医院(MGH)的心脏病专家。 哈佛医学院医学讲师，NHLBI赞助的T32培训的先前实习生 布里格姆妇女医院的格兰特。该奖项的主要目标是让候选人获得 成为一名成功的独立内科医生-科学家所需的培训和技能。他长期的职业生涯 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。 克隆性造血潜能不明(CHIP)指的是含有 白血病相关基因的获得性突变。CHIP易于加速动脉粥样硬化。在Dr。 霍尼格伯格的初步工作表明，有过早更年期病史的女性更容易患上 芯片增加1.4倍，且该芯片与绝经后妇女心血管疾病的发生独立相关。他 现在建议检验CHIP是早产儿妇女加速心血管疾病的关键介质这一假设 使用多种互补方法评估绝经年龄。在目标1中，他将更年期的年龄联系起来 随着时间的推移芯片克隆的扩展和具有序列下一代测序的队列中的事件心血管疾病。 在目标2中，他将使用大型蛋白质组数据集来发现和验证CHIP和CHIP的新蛋白质生物标记 测试这些蛋白在早绝经期相关心血管疾病中的作用。在《目标3》中，他将使用机器 培训、验证和测试芯片风险分类器的学习方法，以指导女性的芯片筛查。 拟议的培训计划涉及基因组学专家普拉迪普·纳塔拉扬博士的主要指导 和动脉粥样硬化性心血管疾病的预防，以及 妇女健康倡议和妇女更年期、性激素和心血管疾病方面的专家。两位导师都是 热心支持霍尼格伯格博士的职业发展。培训计划还包括 杰出科学咨询委员会，包括蛋白质组学和多组学研究专家(Dr。 罗伯特·格斯滕，贝丝以色列女执事医疗中心)，克隆性造血和髓系恶性肿瘤(Dr。 Dana-Farber癌症研究所的Benjamin Ebert)，炎症和血管生物学(Peter Libby博士，Brigham 和机器学习(普尼特·巴特拉博士，麻省理工学院和哈佛大学博德研究所)。这个 候选人将利用麻省理工学院、哈佛大学、麻省理工学院和 远大研究所正在努力完成他提出的培训和研究计划。霍尼格伯格博士的结构 培训计划将发展必要的技能，以从事与他的导师不同的研究计划 并将帮助他转变为一名独立的、由R01资助的内科科学家。

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.