The Role of SECTM1 in Monocyte Biology and Atherosclerosis

SECTM1 在单核细胞生物学和动脉粥样硬化中的作用

• 批准号: 10525199
• 负责人: Usman A. Tahir
• 金额: $ 16.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525199
• 关键词: AKT Signaling Pathway; Advisory Committees; Animal Disease Models; Animal Model; Area; Arterial Fatty Streak; Atherosclerosis; Back; Basic Science; Bioinformatics; Biological; Biological Markers; Biological Models; Biology; Bone Marrow; CD36 gene; Cardiovascular Diseases; Cardiovascular system; Chemotaxis; Chronic; Computational Science; Control Animal; Coronary heart disease; Data; Databases; Development; Developmental Process; Discipline; Disease; Disease Pathway; Disease model; Epidemiology; FRAP1 gene; Foam Cells; Functional disorder; Future; Generations; Genetic; Genetic Databases; Genomics; Goals; Hematopoiesis; Homologous Gene; Human; Human Genetics; In Vitro; Inflammation; Inflammatory; Integral Membrane Protein; Investigation; Israel; Jackson Heart Study; K-Series Research Career Programs; Knockout Mice; Lesion; Leukocytes; Mediating; Mediator of activation protein; Medical center; Medicine; Mendelian randomization; Mentors; Mentorship; Molecular Profiling; Mus; Participant; Pathway interactions; Phagocytosis; Pilot Projects; Plasma; Preventive therapy; Preventive treatment; Process; Proteins; Proteome; Proteomics; Proto-Oncogene Proteins c-akt; Proxy; Publishing; Recombinants; Research; Residual state; Risk; Risk Factors; Role; Sepsis; Signal Transduction; Systems Biology; Techniques; Technology; Testing; Training; Training Programs; Translating; Work; atherogenesis; biomedical informatics; burden of illness; catalyst; cell motility; chemokine; cohort; design; follow-up; functional genomics; genetic analysis; genetic variant; in vivo; insight; instructor; instrument; laboratory experience; macrophage; medical schools; monocyte; mortality; mouse model; novel; oxidized low density lipoprotein; progenitor; recruit; skills; training opportunity; uptake; vascular inflammation; western diet

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.

项目总结/摘要 该提案详细介绍了一个全面的培训计划， 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提供新的洞察动脉粥样硬化的病理生理学， 可以在小动物模型中进行机械测试。候选人是哈佛大学的医学讲师 医学院和贝斯以色列女执事医疗中心心血管遗传学主任。的 概述的建议建立在候选人在生物信息学方面的强大背景上， 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。候选人的导师是一位著名的使用组学进行分子分析的专家 技术和逆转新的发现回到小动物疾病模型的实验室。的 候选人的科学咨询委员会拥有出色的指导记录和广泛的 单核细胞生物学、动脉粥样硬化小鼠模型、人类遗传学和生物信息学方面的专业知识。 拟议的研究建立在初步研究的基础上，初步研究显示SECTM 1与一个不良的 研究了具有单核细胞趋化因子活性和巨噬细胞吞噬作用调节剂的蛋白质， 在杰克逊心脏研究中使用蛋白质组分析与冠心病的发展有关。的 申请人现在提出检验SECTM 1是单核细胞生物学的新调节物的假设， 有助于动脉粥样硬化形成的小鼠疾病模型。在目标1中，申请人将 确定SECTM 1a对骨髓中单核祖细胞增殖的影响， 相关路径。在目标2中，申请人将评估SECTM 1a对动脉粥样硬化病变的作用 小鼠模型中的形成。在目标3中，申请人将测试SECTM 1与其他 使用孟德尔随机化研究的循环蛋白质，为SECTM 1相关途径的新生物学提供信息 并将为未来在小动物模型中的机制研究提供跳板。 冠心病仍然是世界范围内死亡的主要原因， 我们对疾病途径和预防性治疗的理解的进步。大量的 有证据表明炎症是疾病残余负担的关键因素，单核细胞 成为这些过程的重要媒介。该提案旨在利用功能基因组学和一个系统 描绘动脉粥样硬化发展的新炎症通路的生物学方法 这有可能成为冠心病预防性治疗的新靶点。