Cellular Mechanisms of Mac-1 Mediated Atheroprotection

标题：Mac-1介导的动脉粥样硬化保护作用的细胞机制 摘要 简介：本提案概述了一个为期五年的培训计划，以支持我过渡到一个独立的 在研究Mac-1整合素（CD 11b/CD 18）在动脉粥样硬化中的作用时， 发展和并发症。候选人：我以优异的成绩完成了药学博士学位， Creighton大学，然后于2016年5月在迈阿密大学开始博士后研究。 在博士后培训期间，我将专业知识扩展到基础和临床血管研究，发表了14篇论文。 在此期间，还有三份手稿正在审查中。我最近被提升为研究助理 迈阿密大学米勒医学院外科教授。职业生涯 发展计划：我的导师和我已经制定了一个计划，建立在我以前的培训，以获得 一套多样化的技术和领导技能，这将提高我成为一个独立的轨迹 调查员这些包括显微外科手术，大规模细胞计数，骨髓移植， 课程指导委员会：我将与多学科专家团队（血管外科、血管 生物学、免疫学和整合素生物学），他们将在我过渡到 独立我的导师和顾问都是各自领域公认的研究人员， 优秀的资金记录，出版物，和指导。我们同意我作为资深作者发表 自从我开始K 08训练以来，我一直在努力加快我向独立的过渡。环境/体制 支持：我有我的部门的充分承诺，这将确保实验室和办公空间，95% 保护研究、支持人员的时间，并充分利用设备和共享资源。研究 我的总体科学目标是找到更好的治疗动脉粥样硬化的方法， 建立Plaques。我的中心假设是Mac-1的激活通过以下方式降低动脉粥样硬化的负担： 减少单核细胞浸润并通过抑制巨噬细胞表型促进促消退， IL-13受体。这一假设是建立在使用药理学Mac-1激动剂的强有力的初步数据基础上的 和一种新的Mac-1激活的敲入模型，两种方法都支持动脉粥样硬化保护作用， Mac-1受体我将在三个具体目标中检验我的假设，这三个目标将决定Mac-1：1）控制 在早期疾病中的动脉粥样硬化形成和单核细胞募集，2）调节斑块中的巨噬细胞分化， 和3）促进炎症消退和现有损伤中巨噬细胞的流出。预期成果： 有必要的研究工具和资源，以完成我的研究计划中概述的建议。我 我希望在我培训的头三年里至少发表三篇高质量的手稿。我打算申请 我的第一个R 01在第四年，并成为一个完全资助的调查员结束时，K 08的五年培训 期

TITLE: Cellular mechanisms of Mac-1 mediated atheroprotection ABSTRACT Introduction: This proposal outlines a five-year training program to support my transition into an independent pharmacist-scientist, while studying the role of the Mac-1 integrin (CD11b/CD18) in atherosclerosis development and complications. Candidate: I completed a Doctor of Pharmacy degree with honors at Creighton University prior to beginning a postdoctoral fellowship at the University of Miami in May of 2016. During my postdoctoral training, I expanded my expertise to basic and clinical vascular research, publishing 14 manuscripts and three more under review during this period. I was recently promoted to Research Assistant Professor in the Department of Surgery, Miller School of Medicine at the University of Miami. Career development plan: My mentors and I have put together a plan that builds upon my previous training to acquire a diverse set of technical and leadership skills that will enhance my trajectory toward becoming an independent investigator. These include microsurgery, mass cytometry, bone marrow transplantation, and grantsmanship courses. Mentoring committee: I will work with a multidisciplinary team of experts (vascular surgery, vascular biology, immunology, and integrin biology) who will provide mentorship and advice during my transition to independence. My mentors and advisors are recognized investigators in their respective fields with an excellent record of funding, publications, and mentorship. We have agreed that I will publish as senior author since the beginning of my K08 training to speed up my transition to independence. Environment/Institutional support: I have the full commitment of my department, which will ensure laboratory and office space, 95% protected time for research, support personnel, and full access to equipment and shared resources. Research plan: My overall scientific goal is to find better therapies for atherosclerosis and to potentially help regress established plaques. My central hypothesis is that Mac-1 activation decreases atherosclerotic burden by reducing monocyte infiltration and promoting a pro-resolving macrophage phenotype through inhibition of the IL-13 receptor. This hypothesis is built upon strong preliminary data using a pharmacological Mac-1 agonist and a novel knock-in model of Mac-1 activation, with both approaches supporting an atheroprotective role for the Mac-1 receptor. I will test my hypothesis in three specific aims that will determine if Mac-1: 1) controls atherogenesis and monocyte recruitment in early disease, 2) modulates macrophage differentiation in plaques, and 3) promotes inflammation resolution and efflux of macrophages in existing lesions. Expected outcomes: I have the necessary research tools and resources to complete my research plan as outlined in the proposal. I expect to publish at least three top-quality manuscripts during the first three years of my training. I plan to apply for my first R01 in year four and to become a fully funded investigator by the end of the K08’s five-year training period.