Pericytes, pathological angiogenesis and diabetic retinopathy

描述(申请人提供)：虽然糖尿病视网膜病变伴发的血管并发症早已被认识到，但调控病理性血管生成的分子和细胞事件仍然知之甚少。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发挥的重要作用，但控制这些细胞-细胞相互作用的机制尚不清楚。重要的是，周细胞在病理性血管生成启动过程中控制微血管动力学所起的调节作用在很大程度上仍不清楚。事实上，最近在首席研究员实验室开展的工作有力地表明，周细胞在调节糖尿病期间病理性血管生成的发生和发展中发挥着关键作用。这一范式转换假说的核心是初步发现，周细胞Rho GTP和鞘氨醇-1磷酸依赖的信号控制着维持体内内皮细胞生长停滞所需的机械力-化学耦合。作为这一探索性研究计划的特定目标，实验试图验证这一假说，而成功的结果将揭示那些未知的上游信号和下游效应因子，它们控制着负责调控病理性血管生成和增殖性糖尿病视网膜病变的周细胞依赖的启动事件。 公共卫生相关性：这项探索性研究计划的成功结果将提供被认为对我们理解调控糖尿病或衰老期间病理性血管生成的分子和细胞成分至关重要的关键缺失信息。预期的发现不仅将使人们对控制人类微血管病变形成的病理进展的机制有了新的认识，而且预期的结果将为开发目前尚不存在的创新的抗血管生成治疗方法提供机会。

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.