Local Retinal Vasoregulatory Mechanisms

描述（由申请人提供）：视网膜血管疾病是美国失明和视力障碍的重要原因。来自眼科研究的证据表明，由血流调节和/或血管舒缩功能异常引起的组织缺血引发或促成了许多眼部疾病的发病机制。间接证据表明，血流的自动调节发生在视网膜血管；然而，控制视网膜血流的潜在机制尚不清楚。我们的长期目标是改善与视网膜血流调节受损有关的视网膜疾病的预防和治疗。为了达到这一目标，需要对视网膜微血管的基本血管舒缩行为有一个基本的了解。在本研究计划中，我们设计了一个综合方案来表征视网膜小动脉局部血管调节现象（即肌源性和血流依赖性反应），并在视网膜小动脉网络的单个微血管水平上研究这两种反应的相互作用。该研究的中心假设是，视网膜小动脉对压力（即肌源性反应）和血流（即剪切应力诱导的血管舒张）的刺激以一种大小依赖的方式积极响应。实验将在猪视网膜小动脉的不同分支顺序中进行，使用分离的空心血管技术，使压力和流量能够独立控制。内皮细胞和细胞通路参与血管调节的作用将被确定。郭立国教授是K08奖的导师，他之前建立了这种新颖的分离血管技术，用于研究冠状动脉微血管。在他的指导下，候选人获得了支持所提出的假设的初步数据。我们期望这些实验的结果将为视网膜微循环局部血管舒缩调节机制提供新的见解，并最终允许开发新的策略来预防和治疗与微血管功能障碍相关的视网膜疾病。此外，这项K08奖将允许首席研究员获得专业知识和知识的保护时间，这对他成为眼科血管研究领域的独立研究者至关重要。

DESCRIPTION (provided by applicant): Retinal vascular diseases are a significant cause of blindness and visual impairment in the United States. Evidence from ophthalmic research suggests that tissue ischemia resulting from abnormal blood flow regulation and/or vasomotor function initiates or contributes to the pathogenesis of many ocular diseases. Indirect evidence indicates that autoregulation of blood flow occurs in the retinal vasculature; however, the underlying mechanisms that control retinal blood flow are not known. Our long-term objective is to improve the prevention and therapy of retinal diseases that are linked to impaired blood flow regulation in the retina. To reach this goal, a fundamental understanding of basic vasomotor behavior of retinal microvasculature is required. In this research proposal, an integrative plan was designed to characterize the local vasoregulation phenomena (i.e., myogenic and flow-dependent responses) in retinal arterioles and to study the interaction of these two responses at the single microvessel level in the retinal arteriolar network. The central hypothesis for the proposed research is that retinal arterioles actively respond, in a size-dependent manner, to stimulation by pressure (i.e., myogenic response) and flow (i.e., shear stress-induced vasodilation). The experiments will be performed in various branching orders of porcine retinal arterioles using isolated, cannulated vessel techniques to allow pressure and flow to be independently controlled. The role of endothelium and cellular pathways involved in vasoregulation will be determined. Professor Lih Kuo, the mentor for this K08 Award, previously established this novel isolated vessel technique for the study of coronary microvessels. Under his supervision, the candidate has obtained preliminary data that support the proposed hypothesis. Our expectation is that the results of these experiments will provide new insights into the local vasomotor regulatory mechanisms in the retinal microcirculation and ultimately allow for the development of new strategies to prevent and treat retinal diseases associated with microvascular dysfunction. In addition, this K08 Award will allow for protected time for the principal investigator to acquire the expertise and knowledge which are essential to his becoming an independent investigator in the area of ophthalmic vascular research.