The Role of SECTM1 in Monocyte Biology and Atherosclerosis

项目摘要/摘要 这项提案详细说明了一项针对#年职业发展指导奖的综合培训计划。 功能基因组学和系统生物学及其在心血管疾病中的应用。申请人寻求 利用蛋白质组学和人类遗传学为动脉粥样硬化的病理生理学提供新的见解 可以在小动物模型上进行机械测试。这位候选人是哈佛大学的医学讲师 贝丝·以色列女执事医学中心心血管遗传学主任。这个 概要提案建立在候选人在生物信息学方面的强大背景之上，他的硕士学位是 从哈佛医学院的生物医学信息学到新的专业领域：计算基因组学和 小动物模型系统。这位候选人的导师是使用OMIC进行分子图谱分析的知名专家 在疾病的小动物模型中，技术和追溯翻译新发现回到长凳上。这个 候选人的科学咨询委员会拥有卓越的导师记录和广泛的 擅长单核细胞生物学、小鼠动脉粥样硬化模型、人类遗传学和生物信息学。 这项拟议的研究建立在初步研究的基础上，该研究表明SECTM1与一种不良的 研究了具有单核细胞趋化因子活性和巨噬细胞吞噬调节功能的蛋白质， 随着冠心病的发展，在杰克逊心脏研究中使用蛋白质组学图谱。这个 申请人现在提议测试SECTM1是单核细胞生物学的新调节因子和 使用小鼠疾病模型促进动脉粥样硬化的形成。在目标1中，申请者将 检测SECTM1a对骨髓单核细胞祖细胞增殖的影响及其机制 关联的路径。在目标2中，申请者将评估SECTM1a对动脉粥样硬化病变的影响。 在小鼠模型中形成。在目标3中，申请人将测试SECTM1与其他 利用孟德尔随机研究为SECTM1相关通路的新生物学提供信息的循环蛋白 并将为未来在小动物模型中进行机械学研究提供跳板。 冠心病仍然是全球死亡的主要原因，尽管有大量的 我们对疾病途径和预防性治疗的理解的进步。一大堆 有证据表明，炎症是单核细胞疾病残留负担的关键因素。 成为这些进程的重要调解人。该提案旨在使用功能基因组学和一种系统 用生物学方法描绘动脉粥样硬化发生发展的新炎症途径 这有可能成为冠心病预防性治疗的新靶点。

PROJECT SUMMARY /ABSTRACT This proposal details a comprehensive training program for a mentored career development award in functional genomics and systems biology and its application to cardiovascular disease. The applicant seeks to use proteomics and human genetics to provide novel insight into the pathophysiology of atherosclerosis that can be tested, mechanistically in small animal models. The candidate is an Instructor of Medicine at Harvard Medical School and the Director of Cardiovascular Genetics at Beth Israel Deaconess Medical Center. The outlined proposal builds on the candidate’s strong background in bioinformatics following his Master of Biomedical Informatics from Harvard Medical School, to new areas of expertise: computational genomics and small animal model systems. The candidate’s mentor is a renowned expert in molecular profiling using omic technologies and retro-translating novel findings back to the bench in small animal models of disease. The candidate’s scientific advisory committee has a distinguished track record of mentorship and extensive expertise in monocyte biology, murine models of atherosclerosis, human genetics and bioinformatics. The proposed research builds on preliminary studies showing an association of SECTM1, a poorly studied protein with proposed chemokine activity for monocytes and regulator of macrophage phagocytosis, with the development of coronary heart disease in the Jackson Heart Study using proteomic profiling. The applicant now proposes to test the hypothesis that SECTM1 is novel regulator of monocyte biology and contributes to atherosclerosis formation using a murine model of disease. In Aim 1, the applicant will determine the effect of SECTM1a on the proliferation of monocyte progenitors in the bone marrow and its associated pathways. In Aim 2, the applicant will assess the effect of SECTM1a on atherosclerosis lesion formation in mouse models. In Aim 3, the applicant will test the causal association of SECTM1 with other circulating proteins using Mendelian randomization studies to inform new biology of SECTM1-related pathways in humans and will provide a springboard for future mechanistic studies in small animal models. Coronary heart disease remains the leading cause of mortality worldwide, despite the substantial advancements in our understanding of disease pathways and preventative treatments. A large body of evidence has implicated inflammation as a key contributor to the residual burden of disease, with monocytes being important mediators of these processes. The proposal aims to use functional genomics and a systems biology approach towards delineating novel inflammatory pathways towards development of atherosclerosis that has the potential for new targets for preventative treatments for coronary heart disease.