Cellular and molecular mechanisms of endothelial repair and atherosclerosis

内皮修复和动脉粥样硬化的细胞和分子机制

• 批准号: 8586555
• 负责人: Jason Ciril Kovacic
• 金额: $ 12.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-12 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586555
• 关键词: Address; Adult; Age; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arterial Injury; Atherosclerosis; Biology; Blood Vessels; Bone Marrow Cells; Bone Marrow Transplantation; Bromodeoxyuridine; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cell Count; Cells; Cessation of life; Clinical; Clinical Medicine; Clinical Research; Contractile Proteins; Coupled; Data; Development; Endothelial Cells; Endothelium; Epidemic; Event; Failure; Fibroblasts; Flow Cytometry; Fluorescence Microscopy; Fostering; Future; Gene Chips; Gene Expression Profile; Genes; Goals; Harvest; Homeostasis; Immunofluorescence Microscopy; In Vitro; Inflammation; Injury; Kinetics; Label; Location; Maintenance; Maps; Mediating; Mentors; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myofibroblast; Necrosis; Osteoblasts; Pathway interactions; Phenotype; Play; Prevention; Process; Proliferating; Proteins; Public Health; Research; Research Project Grants; Resolution; Role; Rupture; Seeds; Senile Plaques; Shoulder; Signal Transduction; Smooth Muscle Myocytes; Societies; Speed; Stroke; Structure; System; Tamoxifen; Techniques; Thick; Thrombosis; Time; Tissues; Training; Transgenic Mice; Tunica Adventitia; Vascular Diseases; Viral Vector; Wound Healing; arterial remodeling; atherothrombosis; base; career; career development; cell type; defined contribution; design; femoral artery; fighting; in vivo; injury and repair; insight; interest; intima media; laser capture microdissection; migration; mortality; mouse model; neutralizing antibody; normal aging; novel; pre-clinical; programs; promoter; receptor; repaired; research study; skills; small hairpin RNA; vector

DESCRIPTION (provided by applicant): The purpose of this proposal is to launch the independent research career of an interventional cardiologist who wishes to focus on identifying novel molecular mechanisms underlying arterial repair and atherosclerosis. The overall scientific aim is to provide important insights towards deriving targeted strategies to fight cardiovascular disease. To achieve this, the Candidate will couple training in a range of molecular and cell profiling techniques with a structured program of career developmental activities. The Candidate will be supervised by a dedicated team of mentors and advisors who will oversee the proposed research project and career development program. There has been a paucity of significant breakthroughs in our understanding of vascular disease and atherosclerosis in recent years. While incremental progress has been made, the field continues to search in earnest for ways to stabilize atherosclerotic plaques and reduce cardiovascular disease. Given that atherothrombosis remains the #1 killer in Western society, this is an urgent and unmet clinical need. Founded upon on compelling preliminary data, this proposal is a two-pronged systematic approach to address this problem. The role of the endothelium and of endothelial to mesenchymal cell transition in normal vascular biology and atherosclerosis is the focal point of this proposal. In Specific Aim 1, using unique mouse models to track endothelial cells as they migrate and even change their phenotype, the Candidate will characterize key cell types and identify new molecular pathways responsible for endothelial homeostasis and repair. These are critical questions to address, as the failure to properly repair the endothelium leads to arterial thrombosis, vascular occlusion and tissue death. In Specific Aim 2, focused and detailed experiments will explore the cellular and molecular processes that underpin atherosclerosis. Specifically, the Candidate will investigate the ability of endothelial cells to switch their celluar phenotype to become smooth muscle cells, fibroblasts or other cells that drive atherosclerosis. This project will define the extent of this 'cell switching' and will unlock ways to manipulate thi process with the goal of developing novel and more efficacious treatment options. In addition, these experiments will be used to train the Candidate in the techniques of laser-capture microdissection, gene chip analysis, flow cytometry and the use of viral vectors. This program will serve as the seed for future molecular studies and also for potential pre-clinical and ultimately clinical studies targeting atherosclerosis and vascular disease. The relevance of this project to clinical medicine and society is significant. Here, we will investigate the cellular and molecular mechanisms dictating cardiovascular morbidity and mortality, with a view to making meaningful inroads into the prevention and treatment of this epidemic.

描述（由申请人提供）：该提案的目的是启动介入心脏病专家的独立研究职业，他们希望专注于识别动脉修复和动脉粥样硬化的新分子机制。总体科学目的是为推导针对心血管疾病的有针对性策略提供重要的见解。为了实现这一目标，候选人将在一系列分子和细胞分析技术中将培训与职业发展活动的结构化计划相结合。候选人将由一个专门的导师和顾问团队监督，他们将监督拟议的研究项目和职业发展计划。 近年来，我们对血管疾病和动脉粥样硬化的理解中存在很大的突破。尽管已经取得了增长的进步，但该领域继续认真搜索稳定动脉粥样硬化斑块并减少心血管疾病的方法。鉴于动脉粥样硬化仍然是西方社会中排名第一的杀手，这是紧急且未满足的临床需求。该建议是基于引人注目的初步数据，是一种解决此问题的两种基础的系统方法。在正常血管生物学和动脉粥样硬化中，内皮和内皮对间充质细胞转变的作用是该建议的焦点。在特定的目标1中，使用独特的小鼠模型在迁移甚至改变表型时跟踪内皮细胞，候选人将表征关键细胞类型，并确定负责内皮稳态和修复的新分子途径。这些是要解决的关键问题，因为未能正确修复内皮会导致动脉血栓形成，血管阻塞和组织死亡。在特定的目标2中，集中和详细的实验将探索支撑动脉粥样硬化的细胞和分子过程。具体而言，候选人将研究内皮细胞切换其均匀表型的能力，成为平滑肌细胞，成纤维细胞或其他驱动动脉粥样硬化的细胞。该项目将定义此“细胞切换”的程度，并将以开发新颖和更有效的治疗选择的目的来解锁操纵该过程的方法。此外，这些实验将用于训练候选者，以激光捕获显微解剖，基因芯片分析，流式细胞仪和使用病毒载体的使用。该计划将作为未来分子研究的种子，以及针对动脉粥样硬化和血管疾病的潜在临床前和最终临床研究的种子。该项目与临床医学和社会的相关性很重要。在这里，我们将研究细胞和 决定心血管发病率和死亡率的分子机制，以期有意义地侵犯了这种流行病的预防和治疗。