Integrin-Triggered Signaling and Macrophage Mode Switching in Atherosclerosis

描述(申请人提供)：动脉粥样硬化是一个具有重大临床后果的病理过程。巨噬细胞是动脉粥样硬化的重要介质，但巨噬细胞影响动脉粥样硬化的细胞和分子机制的关键方面尚不清楚。被称为整合素的细胞表面受体可以指导巨噬细胞的许多功能，Alenghat博士已经发现了一种新的巨噬细胞特有的信号通路，它作用于整合素的下游，是正常的巨噬细胞迁移、趋化和细胞骨架重塑所必需的。然而，与许多其他巨噬细胞信号缺陷不同的是，该途径中关键蛋白Skap2的缺失加剧了小鼠模型的动脉粥样硬化。因此，这种整合素介导的途径似乎具有动脉粥样硬化保护作用。巨噬细胞如何既负责推动动脉粥样硬化，又负责限制或调节炎症过程？阿伦哈特博士的研究结果表明，控制巨噬细胞表型的是基于整合素的加工水平。根据到目前为止的工作，Skap2的S信号伙伴包括一种主要的抑制蛋白-Sirp？，它由巨噬细胞中的整合素信号控制。了解这些信号控制炎症(激活)和抗炎(抑制)模式之间的平衡的机制，可能会为治疗动脉粥样硬化提供合理的新方法。在这里，Alenghat博士假设，依赖于SIRP？、Skap2和其他分子伙伴的整合素介导的通路在巨噬细胞中引导信号开关，这些通路可能通过调节肿瘤内巨噬细胞的动力学来调节动脉粥样硬化的炎症成分。在三个具体目标中，Alenghat博士将：(1)如何描述Skap2/SIRP？模块通过抑制和激活途径引导信号，以调节巨噬细胞的细胞骨架重塑；(2)使用小鼠模型来确定这些整合素介导的途径控制动脉粥样硬化的炎症成分的机制；以及(3)开发创新的技术来研究专门的体外和肿瘤内巨噬细胞动力学，以了解巨噬细胞如何维持病变的动态平衡。该项目的成功完成将为动脉粥样硬化的潜在机制提供新的见解，并可能有助于确定治疗干预的新靶点，以治疗或预防这一过程。阿伦哈特博士是一名内科科学家，分别在哈佛医学院和哈佛生物物理学项目完成了医学和研究生教育。他在布里格姆妇女医院接受内科和心血管内科临床培训，并在这两个领域都获得了董事会认证。他是哈佛医学院生物化学和分子药理学讲师和医学讲师，也是退伍军人管理局波士顿医疗系统的心脏病专家。阿伦哈特博士拥有血管生物学、整合素信号和机械转导方面的研究背景，他的长期目标是作为一名学术心脏病专家和该领域的领先者，执行和指导心血管基础和翻译研究。他的近期目标是以他目前的调查结果为基础，提出新的调查方向，这将巩固他在该领域的专业知识，并促进他从受指导的调查员转变为独立调查员。具体地说，他将获得几项新的研究技能，开发评估动脉粥样硬化病变的创新技术，与他的导师和专家顾问小组密切互动，在多个地点以演讲和出版物的形式展示他的工作，并通过哈佛催化剂计划获得进一步的培训，该计划专门针对向独立的过渡。他将与他的导师大卫·戈兰博士在哈佛医学院生物化学和分子药理学系的实验室一起开展工作。这个研究环境拥有所有必要的设施、设备、专业知识和支持性培训，以成功完成该项目。

DESCRIPTION (provided by applicant): Atherosclerosis is a pathologic process with major clinical consequences. Macrophages are important mediators of atherosclerosis, but critical aspects of the cellular and molecular mechanisms by which macrophages affect atherosclerosis are unclear. Cell-surface receptors called integrins can direct many macrophage functions, and Dr. Alenghat has identified a new macrophage-specific signaling pathway that acts downstream of integrins and is required for normal macrophage migration, chemotaxis, and cytoskeletal remodeling. However, unlike many other macrophage signaling defects, the absence of a key protein in this pathway-Skap2-exacerbates atherosclerosis in a mouse model. Therefore, this integrin-mediated pathway appears to be atheroprotective. How can macrophages be responsible both for driving atherosclerosis and for limiting or modulating inflammatory processes? Dr. Alenghat's results point to an integrin-based level of processing that controls macrophage phenotype. Based on work to date, Skap2's signaling partners include one major inhibitory protein-Sirp?-that is controlled by integrin signals in macrophages. Understanding the mechanism by which such signaling controls a balance between inflammatory (activating) and anti- inflammatory (inhibitory) modes may point to rational new approaches for treatment of atherosclerosis. Here, Dr. Alenghat hypothesizes that integrin-mediated pathways dependent on Sirp?, Skap2, and other molecular partners direct a signaling switch in macrophages, and that these pathways modulate the inflammatory component of atherosclerosis, possibly by regulating intralesional macrophage dynamics. In three specific aims, Dr. Alenghat will: (1) characterize how the Skap2/Sirp? module directs signals through inhibitory and activating pathways to modulate macrophage cytoskeletal remodeling; (2) use mouse models to define the mechanism by which these integrin-mediated pathways control the inflammatory component of atherosclerosis; and (3) develop innovative techniques to study specialized in vitro and intralesional macrophage dynamics in order to understand how macrophages maintain lesional homeostasis. Successful completion of this project will provide new insights into the mechanisms underlying atherosclerosis and may aid in the identification of novel targets for therapeutic intervention to either treat or prevent this process. Dr. Alenghat is a physician-scientist who completed his medical and graduate education at Harvard Medical School and the Harvard Biophysics Program, respectively. He trained clinically in internal medicine and cardiovascular medicine at Brigham and Women's Hospital and is board certified in both fields. He is Instructor in Biological Chemistry and Molecular Pharmacology and Instructor in Medicine at Harvard Medical School, and he is a staff cardiologist at VA Boston Healthcare System. With a research background in vascular biology, integrin signaling, and mechanotransduction, Dr. Alenghat's long-term goal is to perform and direct cardiovascular basic and translational research as an academic cardiologist and a leader in his field. His immediate goal is to build on his current findings with new investigative directions, which would solidify his expertise in the field and facilitate his transition from mentored to independent investigator. Specifically, he wil acquire several new research skills, develop innovative techniques to assess atherosclerotic lesions, interact closely with both his mentor and an expert panel of advisors, present his work in the form of talks and publications in multiple venues, and acquire further training through the Harvard Catalyst Program that is specifically geared to facilitate the transition to independence. He will conduct his work with the laboratory of his mentor, Dr. David Golan, in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. This research environment has all the necessary facilities, equipment, expertise, and supportive training to complete the project successfully.