Integrin-Triggered Signaling and Macrophage Mode Switching in Atherosclerosis

描述（由申请人提供）：动脉粥样硬化是一种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。称为整合素的细胞表面受体可以指导许多巨噬细胞功能，Alenghat博士已经确定了一种新的巨噬细胞特异性信号通路，该通路作用于整合素的下游，并且是正常巨噬细胞迁移，趋化性和细胞骨架重塑所必需的。然而，与许多其他巨噬细胞信号传导缺陷不同，在小鼠模型中，该途径中关键蛋白Skap 2的缺失加剧了动脉粥样硬化。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驱动动脉粥样硬化又负责限制或调节炎症过程？Alenghat博士的研究结果指出，基于整合素的加工水平控制着巨噬细胞的表型。基于迄今为止的工作，Skap 2的信号伙伴包括一个主要的抑制蛋白-Sirp？由巨噬细胞中的整合素信号控制。了解这种信号传导控制炎症（激活）和抗炎（抑制）模式之间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。在此，Alenghat博士假设整合素介导的途径依赖于Sirp？，Skap 2和其他分子伴侣指导巨噬细胞中的信号转换，这些途径可能通过调节病变内巨噬细胞动力学来调节动脉粥样硬化的炎症成分。在三个具体的目标，博士Alenghat将：（1）如何描述Skap 2/Sirp？该模块指导信号通过抑制和激活途径来调节巨噬细胞细胞骨架重塑;（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;和（3）开发创新技术来研究专门的体外和病灶内巨噬细胞动力学，以了解巨噬细胞如何维持病灶内稳态。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，并可能有助于识别治疗干预的新靶点，以治疗或预防这一过程。Alenghat博士是一位内科医生兼科学家，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过内科和心血管内科的临床培训，并在这两个领域获得了董事会认证。他是哈佛医学院的生物化学和分子药理学讲师以及医学讲师，他是VA波士顿医疗保健系统的心脏病专家。凭借血管生物学，整合素信号传导和机械转导的研究背景，Alenghat博士的长期目标是作为学术心脏病专家和该领域的领导者执行和指导心血管基础和转化研究。他的近期目标是在现有调查结果的基础上，提出新的调查方向，这将巩固他在该领域的专门知识，并促进他从接受指导的调查员过渡到独立调查员。具体而言，他将获得几个新的研究技能，开发创新技术来评估动脉粥样硬化病变，与他的导师和顾问专家小组密切互动，在多个地点以讲座和出版物的形式展示他的工作，并通过专门面向促进向独立过渡的哈佛催化剂计划获得进一步培训。他将在哈佛医学院生物化学和分子药理学系的导师大卫戈兰博士的实验室开展工作。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.