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: 10680450
• 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/10680450
• 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; Macrophage; Mediating; Mediator; Medical center; Medicine; Mendelian randomization; Mentors; Mentorship; Molecular Profiling; Mus; PIK3CG gene; Participant; Pathway interactions; Phagocytosis; Pilot Projects; Plasma; Predisposition; Preventive therapy; Preventive treatment; Process; Proliferating; 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; 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.

项目摘要 /摘要 该提案详细介绍了一项全面的培训计划，旨在获得指导的职业发展奖 功能基因组学和系统生物学及其在心血管疾病中的应用。该申请寻求 使用蛋白质组学和人类遗传学来对动脉粥样硬化的病理生理学提供新的见解 可以在小型动物模型中进行机械测试。候选人是哈佛的医学教练 贝丝以色列执事医学中心医学院和心血管遗传学主任。这 概述提案以他的主人为基础 从哈佛医学院到新专业领域的生物医学信息学：计算基因组学和 小动物模型系统。候选人的心理是使用OMIC在分子分析方面的著名专家 在小型疾病的小动物模型中，技术和重新翻译的新发现回到了长凳上。这 候选人的科学咨询委员会具有杰出的心态和广泛记录 单核细胞生物学，动脉粥样硬化，人类遗传学和生物信息学的鼠模型的专业知识。 拟议的研究以初步研究为基础，显示了宗派的关联，这是一个差的 烟囱蛋白具有拟议的趋化因子活性，用于单核细胞和巨噬细胞吞噬的调节剂， 在杰克逊心脏研究中使用蛋白质组学分析的冠状动脉疾病的发展。这 现在，申请人提出了检验Sectm1是单核细胞生物学的新调节剂的假设和 使用鼠类疾病模型有助于动脉粥样硬化形成。在AIM 1中，适用的将 确定Sectm1a对骨髓及其单核细胞祖细胞增殖的影响 相关途径。在AIM 2中，适用将评估Sectm1a对动脉粥样硬化病变的影响 鼠标模型中的形成。在AIM 3中，申请人将测试Sectm1的因果关系 使用Mendelian随机研究循环蛋白质，以告知Sectm1相关途径的新生物学 在人类中，将在小动物模型中为未来的机械研究提供跳板。 冠心病仍然是全世界死亡率的主要原因，大多数 我们对疾病途径和预防治疗的理解的进步。一大堆 证据已实施炎症，是疾病残留烧伤的关键因素，单核细胞 是这些过程的重要调解人。该提案旨在使用功能基因组学和系统 生物学方法描述了开发动脉粥样硬化的新型炎症途径 这有可能建立新的冠状动脉疾病治疗靶标。

项目成果

An atlas of genetic scores to predict multi-omic traits.

• DOI: 10.1038/s41586-023-05844-9
• 发表时间: 2023-04
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Xu, Yu;Ritchie, Scott C.;Liang, Yujian;Timmers, Paul R. H. J.;Pietzner, Maik;Lannelongue, Loic;Lambert, Samuel A.;Tahir, Usman A.;May-Wilson, Sebastian;Foguet, Carles;Johansson, Asa;Surendran, Praveen;Nath, Artika P.;Persyn, Elodie;Peters, James E.;Oliver-Williams, Clare;Deng, Shuliang;Prins, Bram;Luan, Jian'an;Bomba, Lorenzo;Soranzo, Nicole;Di Angelantonio, Emanuele;Pirastu, Nicola;Tai, E. Shyong;van Dam, Rob M.;Parkinson, Helen;Davenport, Emma E.;Paul, Dirk S.;Yau, Christopher;Gerszten, Robert E.;Malarstig, Anders;Danesh, John;Sim, Xueling;Langenberg, Claudia;Wilson, James F.;Butterworth, Adam S.;Inouye, Michael
• 通讯作者: Inouye, Michael