Pericytes, pathological angiogenesis and diabetic retinopathy

描述（由申请人提供）：虽然糖尿病视网膜病变的血管并发症早已被认识到，但调控病理性血管生成开始和进展的分子和细胞事件仍然知之甚少。而且，虽然最近的工作揭示了微血管内皮细胞和周细胞相互作用在控制毛细血管稳定性和通透性方面的重要作用，但控制这些细胞-细胞相互作用的机制却知之甚少。重要的是，在病理性血管生成过程中，周细胞在控制微血管动力学方面的调节作用在很大程度上仍然未知。事实上，最近在首席研究员实验室开展的工作强烈表明，周细胞在调节糖尿病病理性血管生成的发生和进展中起着关键作用。这一范式转移假说的核心是初步发现周细胞Rho GTP-和鞘氨醇-1磷酸依赖信号控制体内维持内皮细胞生长停滞所需的机械-化学偶联。实验概述了探索性研究计划的具体目标，旨在验证这一假设，而成功的结果将揭示那些未知的上游信号和下游效应物，这些信号和效应物控制着负责调节病理性血管生成和增殖性糖尿病视网膜病变发病的周细胞依赖性启动事件。

DESCRIPTION (provided by applicant): Whereas the vascular complications accompanying diabetic retinopathy have long been recognized, the molecular and cellular events regulating the initiation and progression of pathologic angiogenesis remain poorly understood. And, while recent work has revealed the important role that microvascular endothelial cell and pericyte interactions play in controlling capillary stability and permeability, the mechanisms controlling these cell-cell interactions are poorly understood. Importantly, the regulatory roles that pericytes play in controlling microvascular dynamics during the initiation of pathologic angiogenesis remain largely unknown. Indeed, recent work carried out in the principal investigator's laboratory strongly suggests that pericytes play pivotal roles in regulating the onset and progression of pathologic angiogenesis during diabetes. Central to this paradigm-shifting hypothesis are the preliminary findings that pericyte Rho GTP- and sphingosine-1 phosphate-dependent signaling control the mechano- chemical coupling required to sustain endothelial growth arrest in vivo. Experiments outlined as specific aims for this exploratory research program seek to validate this hypothesis while successful outcomes will unveil those unknown, upstream signals and downstream effectors, which control the pericyte- dependent initiating events responsible for regulating the onset of pathologic angiogenesis and proliferative diabetic retinopathy. PUBLIC HEALTH RELEVANCE: Successful outcomes of this exploratory research program will provide the critical missing information deemed essential for our understanding the molecular and cellular components that regulate the onset and progression of pathologic angiogenesis during diabetes or aging. Anticipated findings will not only enable a newfound awareness for the mechanisms controlling the pathologic progression of microvascular lesion formation in humans, but anticipated results should provide opportunities for the development of innovative anti-angiogenesis therapeutic approaches that are not currently available.