Endothelial Progenitor Cells: Clinical Prognosis

描述（由申请人提供）：内皮损伤引发一系列事件，破坏血管稳态并促进动脉粥样硬化。直到最近，人们才认为内源性修复或再生受损内皮的能力是有限的。现在已知成人外周血中含有内皮祖细胞（EPCs），它们有助于血管修复和再内皮化。早期临床研究提高了EPCs作为心血管疾病（CVD）风险新生物标志物的可能性，但这些研究受到样本量小和缺乏纵向随访的限制。我们假设心血管疾病的易感性是由心血管疾病危险因素介导的内皮损伤和内皮修复之间的平衡决定的，内皮修复部分由内皮细胞决定。我们建议验证以下假设：(1)EPC数量和功能随年龄增长而下降，并与终生暴露于已知心血管疾病危险因素有关；(2)遗传变异影响EPC测度；(3) EPC数量和功能减少与亚临床血管结构和功能改变有关；(4)降低了EPC数量和功能对CVD发展的纵向易感性，超出了传统的危险因素。我们建议在一个大型的前瞻性队列中评估EPCs（约3500名Framingham心脏研究[FHS]参与者参加了Offspring检查8和Omni检查3）。我们的具体目标是：(1)检测EPC数量和功能的临床和遗传相关性（使用体外菌落计数、流式细胞术、迁移试验和3-半乳糖苷酶染色）；(2)探讨EPC特征与亚临床血管结构（颈动脉内膜-中膜厚度[IMT]、颈动脉狭窄）和功能（外周动脉血压计、肱血流介导扩张、血管血压计）的关系；(3)分析EPC特征与CVD流行和发生的关系。拟议的研究代表了FHS，马萨诸塞州总医院（MGH）心脏病科和MGH再生医学中心的研究人员之间的合作。FHS队列提供了一个大的、单一地点的、以社区为基础的中年和老年人样本，这些人在过去30年里被广泛地描述了特征，并持续监测新的心血管疾病事件。结合研究者的专业知识和表型良好的队列，应该可以严格检查内皮修复、亚临床CVD和CVD风险之间的关系。身体修复受损血管的能力异常可能会增加患心脏病和中风的风险。如果这一假设是正确的，那么检查血液中循环的“修复”细胞，即内皮祖细胞，可能会深入了解个体对心血管疾病的易感性，并可能提出新的治疗方法。

DESCRIPTION (provided by applicant): Endothelial injury sets in process a chain of events that disrupt vascular homeostasis and promote atherosclerosis. Until recently, it was believed that the endogenous capacity to repair or regenerate damaged endothelium was limited. It is now known that the adult peripheral blood contains a population of endothelial progenitor cells (EPCs) that contribute to vascular repair and re-endothelialization. Early clinical studies raise the possibility that EPCs could serve as a novel biomarker of cardiovascular disease (CVD) risk, but these studies were limited by small sample sizes and lack of longitudinal follow up. We postulate that susceptibility to CVD is determined by the balance between endothelial injury, mediated by CVD risk factors, and endothelial repair, in part determined by EPCs. We propose to test the following hypotheses: (1)'EPC number and function decline with advancing age, and are related to life-long exposure to known CVD risk factors; (2) genetic variation influences EPC measures; (3) reduced EPC number and function are associated with subclinical vascular structural and functional alterations cross-sectionally; and (4) reduced EPC number and function predispose to the development of CVD longitudinally, above and beyond traditional risk factors. We propose to assess EPCs in a large, prospective cohort (approximately 3500 Framingham Heart Study [FHS] participants at Offspring exam 8 and Omni exam 3). Our specific aims are: (1) To examine the clinical and genetic correlates of EPC number and function (using in vitro colony counts, flow cytometry,-migratory assays, and (3-galactosidase staining); (2) To investigate the association of EPC characteristics with subclinical measures of vascular structure (carotid intima-media thickness [IMT], carotid stenosis) and function (peripheral arterial tonometry, brachial flow-mediated dilation, vascular tonometry); and (3) To analyze the relations of EPC characteristics with prevalent and incident CVD. The proposed research represents a collaboration between investigators at the FHS, Massachusetts General Hospital (MGH) Cardiology Division, and MGH Center for Regenerative Medicine. The FHS cohort provides a large, single site, community-based sample of middle-aged and elderly individuals who have been extensively characterized over 3 decades and are under continuous surveillance for new CVD events. The combination of investigator expertise and a well-phenotyped cohort should allow rigorous examination of the relations between endothelial repair, subclinical CVD, and CVD risk. Abnormalities in the body's ability to repair damaged blood vessels may contribute to the risk of heart disease and stroke. If this hypothesis is true, then examination of the circulating "repair" cells in the blood, known as endothelial progenitor cells, may provide insight into an individual's susceptibility to cardiovascular disease and may suggest novel therapeutic approaches.