Cellular Mechanisms of Mac-1 Mediated Atheroprotection

Mac-1介导动脉粥样硬化保护的细胞机制 摘要 简介：这份提案概述了一个为期五年的培训计划，以支持我过渡到独立的 药剂师-科学家，研究Mac-1整合素(CD11b/CD18)在动脉粥样硬化中的作用 发展和并发症。应聘者：我以优异的成绩获得药学博士学位 在2016年5月开始在迈阿密大学攻读博士后之前，他在克雷顿大学工作。 在博士后培训期间，我将自己的专业知识扩展到基础和临床血管研究，发表了14篇 手稿和在此期间正在审查的另外三份手稿。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，以我之前的培训为基础，以获得 一套多样化的技术和领导技能，将增强我成为独立人士的轨迹 调查员。这些技术包括显微外科手术、质量细胞术、骨髓移植和医疗技术。 课程。指导委员会：我将与一个多学科的专家团队(血管外科、血管 生物学、免疫学和整合素生物学)，在我过渡到 独立。我的导师和顾问都是各自领域公认的调查人员， 在资金、出版物和指导方面都有出色的记录。我们已经同意我将以资深作者的身份出版 自从我开始接受K08训练以来，我就加快了向独立的过渡。环境/机构 支持：我得到了我所在部门的全力支持，将确保实验室和办公空间95% 保护研究、支持人员以及完全访问设备和共享资源的时间。研究 计划：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，并有可能帮助动脉粥样硬化的消退 已建立的斑块。我的中心假设是Mac-1激活通过以下方式减少动脉粥样硬化的负担 通过抑制巨噬细胞的活化，减少单核细胞的渗透，促进巨噬细胞的表型分解 IL-13受体。这一假说是建立在使用药理Mac-1激动剂的强大初步数据基础上的。 和一种新的Mac-1激活的敲入模型，这两种方法都支持对动脉粥样硬化的保护作用 Mac-1受体。我将在三个具体目标上测试我的假设，这三个目标将决定Mac-1：1)是否控制 早期疾病中的动脉粥样硬化和单核细胞募集，2)调节斑块中巨噬细胞的分化， 3)促进现有病变中巨噬细胞的炎症消退和外流。预期结果：i 有必要的研究工具和资源来完成我在提案中概述的研究计划。我 预计在我培训的头三年里，至少会发表三篇高质量的手稿。我打算申请 为了我四年级的第一个R01，并在K08‘S五年培训结束时成为一名全额资助的调查员 句号。

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.