Physiology of Retinal Pericytes

视网膜周细胞的生理学

• 批准号: 6623827
• 负责人: DONALD G PURO
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623827
• 关键词: capillary bed; cell cell interaction; cellular pathology; diabetic retinopathy; electron transport; endothelin; enzyme induction /repression; gap junctions; immunocytochemistry; isozymes; laboratory rat; macrophage; mathematical model; microcirculation; protein kinase C; retina circulation disorder; vascular endothelium; vision disorders; voltage /patch clamp

DESCRIPTION (provided by applicant): Our long-range objective is to elucidate the pathophysiological mechanisms that disrupt microvascular function early in the course of diabetic retinopathy. A vital function lost soon after the onset of diabetes is the autoregulatory control of the retinal microcirculation. The resulting inefficiency in the distribution of blood flow compromises the function, and eventually, the viability of retinal neurons, glia and vascular cells. At present, a critical gap in our understanding of how diabetes alters microvascular function is the limited knowledge of the mechanisms by which local vasoactive signals regulate capillary perfusion in the retina. Our proposed studies are based on a new working hypothesis. Namely, voltage changes induced by vasoactive signals that act at distal capillary sites must be transmitted electrotonicly via gap junction pathways to proximal pericytes. This intercellular transmission is necessary because proximal, but not distal, pericytes contain the contractile apparatus necessary to regulate the diameter of the microvascular lumen. Using dual perforated-patch recordings and other techniques, we will compare intercellular communication within pericyte-containing microvessels freshly isolated from retinas of control and diabetic rats. To address the mechanisms by which diabetes disrupts distal-to-proximal communication within the retinal microvasculature, the specific aims of our proposed studies will test the hypotheses that (1) in diabetes a disruption of electrotonic transmission between retinal pericytes compromises the transduction mechanism by which a vasoactive signal acting at a distal capillary site elicits a contraction or relaxation of the proximal portion of a pericyte-containing microvessel, (2) PKC-beta isoforms play a critical role in the mechanism by which gap junction pathways are disrupted in microvessels of the diabetic retina and (3) ET/A endothelin receptors mediate disruption of intercellular communication within diabetic microvessels. Over the long-term, elucidating the mechanisms by which diabetes disrupts the ability of local vasoactive signals to regulate capillary perfusion will facilitate the development of new strategies to ameliorate, and hopefully, prevent sight-threatening complications of this disease.

描述（由申请人提供）：我们的长期目标是阐明 早期破坏微血管功能的病理生理机制 糖尿病视网膜病变的病程。发病后不久就丧失了重要功能 糖尿病的发病机制是视网膜微循环的自动调节。这 导致血流分配效率低下，影响 功能，并最终影响视网膜神经元、神经胶质细胞和血管的活力 细胞。 目前，我们对糖尿病如何改变的理解存在重大差距 微血管功能是其机制的有限知识 局部血管活性信号调节视网膜毛细血管灌注。我们的 拟议的研究基于一个新的工作假设。即电压变化 由作用于远端毛细血管部位的血管活性信号引起的必须是 通过间隙连接途径将电紧张传递至近端周细胞。 这种细胞间传输是必要的，因为近端而非远端 周细胞含有调节直径所需的收缩装置 的微血管腔。使用双穿孔贴片录音和其他 技术，我们将比较细胞间通讯 从对照和视网膜中新鲜分离出的含有周细胞的微血管 糖尿病大鼠。 解决糖尿病破坏远端到近端的机制 视网膜微血管内的通讯，我们的具体目标 拟议的研究将检验以下假设：(1) 在糖尿病中， 视网膜周细胞之间的电紧张传递会损害 血管活性信号作用于远端的转导机制 毛细血管部位引起毛细血管近端部分的收缩或松弛 含有周细胞的微血管，(2) PKC-β亚型在 微血管中间隙连接通路被破坏的机制 糖尿病视网膜和 (3) ET/A 内皮素受体介导的破坏 糖尿病微血管内的细胞间通讯。 从长远来看，阐明糖尿病破坏糖尿病的机制 局部血管活性信号调节毛细血管灌注的能力 促进新战略的制定，以改善，并希望， 预防这种疾病威胁视力的并发症。