Cellular Mechanisms of Mac-1 Mediated Atheroprotection

Mac-1 介导的动脉粥样硬化保护的细胞机制

基本信息

批准号：
10596607
负责人：
Laisel Martinez
金额：
$ 11.5万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-18 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596607
关键词：
Acceleration Acute Address Adhesions Adult Affect Agonist Agreement Animals Apoptotic Arterial Fatty Streak Atherosclerosis Biology Blood Vessels Bone Marrow Transplantation Cardiac Cells Cholesterol Chronic Clinical Cytometry Data Development Development Plans Disease Disease Progression Disease regression Doctor of Pharmacy Endothelium Ensure Environment Equipment Extravasation Fellowship Foam Cells Fostering Funding Genetic Goals Human Resources IL-13Ralpha1 ITGAM gene ITGB2 gene Immunology In Vitro Infiltration Inflammation Inflammatory Institution Integrins Interleukin-13 Interleukin-4 Investigation Ischemia Ischemic Stroke Journals Knock-in Laboratories Leadership Lesion Leukocytes Lipids Macrophage Macrophage-1 Antigen Manuscripts Mediating Mentors Mentorship Microsurgery Modeling Mus Myofibroblast Necrosis Operative Surgical Procedures Outcome Patients Peptide Hydrolases Peripheral arterial disease Phagocytosis Pharmacists Pharmacotherapy Phenotype Population Postdoctoral Fellow Proliferating Public Health Publications Publishing Reactive Oxygen Species Research Research Assistant Research Personnel Resolution Resource Sharing Resources Respiratory Burst Rest Role Scientist Signal Transduction Site Smooth Muscle Myocytes Specificity Speed Stable Disease Surgical Models Testing Time Training Training Programs Tumor Immunity United States Universities Vascular Diseases Work acute coronary syndrome atherogenesis atheroprotective career development cell motility cytokine design efficacy validation in vivo interest interleukin-13 receptor lipid metabolism loss of function medical schools monocyte morphometry multidisciplinary novel novel therapeutic intervention pharmacologic post-doctoral training professor receptor recruit skills tool uptake vascular inflammation

项目摘要

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.

标题：Mac-1的细胞机制介导的动脉保护抽象的简介：该提案概述了一项为期五年的培训计划，以支持我向独立的过渡药剂师科学家，同时研究Mac-1整合素（CD11b/CD18）在动脉粥样硬化中的作用发展和并发症。候选人：我以荣誉完成了药学博士学位克雷顿大学（Creighton University）于2016年5月在迈阿密大学开始博士后奖学金。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，出版14 在此期间，手稿和三个正在审查。我最近被提升为研究助理迈阿密大学米勒医学院手术系教授。职业发展计划：我和我的导师制定了一个计划，该计划是基于我以前的培训来获得的潜水员一套技术和领导技能，将增强我成为独立的轨迹研究者。其中包括显微外科手术，质量细胞仪，骨髓移植和赠款技巧课程。指导委员会：我将与一个多学科专家团队（血管手术，血管生物学，免疫学和整联蛋白生物学），在我过渡到独立。我的导师和顾问在各自的领域都公认资金，出版物和精神制的良好记录。我们已经同意我将以高级作家的身份出版自从我的K08培训开始以加快我过渡到独立性以来。环境/机构支持：我拥有我部门的全部承诺，这将确保实验室和办公空间，95％保护时间，支持人员以及对设备和共享资源的全面访问时间。研究计划：我的整体科学目标是找到更好的动脉粥样硬化疗法，并有助于退缩已建立的斑块。我的中心假设是Mac-1激活下降了动脉粥样硬化伯恩减少单核细胞浸润并通过抑制促进促巨噬细胞表型 IL-13受体。该假设建立在使用药物Mac-1激动剂的强大初步数据的基础上以及Mac-1激活的新型敲门模型，两种方法都支持动脉保护作用 Mac-1受体。我将以三个特定目的测试我的假设，以确定Mac-1是否：1）控制早期疾病中的动脉粥样硬化和单核细胞募集，2）调节斑块中的巨噬细胞分化， 3）促进现有病变中巨噬细胞的注射分辨率和外排。预期结果：我拥有必要的研究工具和资源来完成我的研究计划，如提案中所述。我期望在我的培训的头三年中至少发表三本高质量的手稿。我打算申请对于我在第四年的第一个R01，并在K08的五年培训结束时成为一名资助全额资助的调查员时期。