Retinovascular pathophysiology: focus on proliferative retinopathy

视网膜血管病理生理学：关注增殖性视网膜病

• 批准号: 8774904
• 负责人: DONALD G PURO
• 金额: $ 38.1万
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774904
• 关键词: Address; Adenosine; Affect; Animal Model; Blindness; Blood Vessels; Blood flow; Calcium; Calcium Channel; Caliber; Cells; Clinical; Complex; Complication; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Disease; Functional disorder; Growth; Health; Hypoxia; Image; Knowledge; Lasers; Lead; Mediating; Membrane Potentials; Metabolic; Methodology; Mission; National Eye Institute; Patch-Clamp Techniques; Patients; Perfusion; Photography; Premature Birth; Public Health; Pump; Regulation; Research; Research Project Grants; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Rodent; Series; Signal Transduction; Surface; Testing; Thinking; Time; Tissues; United States National Institutes of Health; Vascular Diseases; Vasodilation; Vasomotor; Vision; Work; base; bevacizumab; constriction; experience; extracellular; improved; innovation; meetings; mouse model; neovascular; neovascularization; novel; novel therapeutic intervention; novel therapeutics; patch clamp; research study; response; retina blood vessel structure; vasoconstriction; voltage

DESCRIPTION (provided by applicant): The proposed research will use a novel experimental strategy to enhance our understanding of the pathophysiology of proliferative retinopathy, which is a sight-threatening complication of diabetes, retinopathy of prematurity and other important disorders. Despite the benefits of laser and anti-VEGF treatments, this complication continues to cause blindness. At present, the development of new therapeutic approaches to the problem of proliferative retinopathy is limited by gaps in knowledge about its pathophysiology. In the quest to better understand the pathophysiology of proliferative retinopathy, which is characterized by aberrant new blood vessel growth on the retinal surface, we hypothesized that pre-retinal neovessels exert a function-altering effect on the intra-retinal vasculature. By causin vascular dysfunction and thereby, compromising the effective adjustment of local perfusion to meet metabolic demand, this newly postulated pathophysiological mechanism may exacerbate retinal hypoxia, which potently stimulates neovascularization. To begin characterization of the functional interactions of pre- and intra-retinal vessels, we preformed preliminary studies utilizing a well-established mouse model of proliferative retinopathy. Building upon our extensive use of the patch-clamp technique to elucidate the functional organization of the retinal vasculature, our initial studies provided the first electrophysiological assessment of pathological neovessels in any tissue. Preliminary data support the new concept that pre-retinal neovessels exert a function-altering effect on intra- retinal vessels. To elucidate mechanisms by which pre-retinal neovessels alter the function of the intra-retinal vasculature, the specific aims of our proposed studies are to test the hypotheses that (1) in proliferative retinopathy, the membrane potential of the intra-retinal vasculature is driven to a high, function-altering level by a hyperpolarizing voltage that is transmitted from pre-retinal neovessels and (2) that proliferative retinopathy fundamentally alters how the retinal vasculature responds to the hypoxia-driven vasoactive signal adenosine. Achieving these specific aims will open up an entirely new line of scientific inquiry into the pathophysiology of proliferative retinopathy. In addition, the proposed research will create new knowledge that is likely to contribute to the development of a new therapeutic strategy for ameliorating vision loss in this disorder. In our opinion, the planned project is highly innovative because it will establish a new experimental approach for understanding proliferative retinopathy and by revealing previously unknown pathophysiological mechanisms, will significantly change current thinking about this vision-threatening disorder. In the long-term, elucidation of how proliferative retinopathy exerts function-altering effects on the intra- retinal vasculature is likely to provide new pharmacological targets for treating this dreaded complication.

描述（由申请人提供）：拟议的研究将使用一种新的实验策略，以提高我们对增殖性视网膜病变的病理生理学的理解，增殖性视网膜病变是糖尿病、早产儿视网膜病变和其他重要疾病的威胁视力的并发症。尽管激光和抗VEGF治疗的好处，这种并发症继续导致失明。目前，发展新的治疗方法的问题，增殖性视网膜病变是有限的知识差距，其病理生理学。 为了更好地了解增生性视网膜病变的病理生理学，其特征是视网膜表面异常的新血管生长，我们假设视网膜前新生血管对视网膜内血管系统产生功能改变作用。通过引起血管功能障碍，从而损害局部灌注的有效调节以满足代谢需求，这种新假设的病理生理机制可能加剧视网膜缺氧，这有力地刺激新血管形成。 为了开始表征视网膜前血管和视网膜内血管的功能相互作用，我们利用成熟的增殖性视网膜病变小鼠模型进行了初步研究。在我们广泛使用膜片钳技术阐明视网膜血管的功能组织的基础上，我们的初步研究提供了第一个病理性视网膜病变的电生理评估。 任何组织中的新生血管初步数据支持视网膜前新生血管对视网膜内血管产生功能改变作用的新概念。为了阐明视网膜前新生血管改变视网膜内血管功能的机制，我们提出的研究的具体目的是检验以下假设：（1）在增殖性视网膜病变中，视网膜内血管的膜电位被驱动到高，通过从视网膜前新生血管传输的超极化电压改变功能水平，以及（2）增殖性视网膜病变从根本上改变了视网膜血管系统对缺氧驱动的血管活性信号腺苷的反应。 实现这些具体目标将开辟一个全新的路线的科学探究增生性视网膜病变的病理生理学。此外，拟议的 研究将创造新的知识，可能有助于开发新的治疗策略，以改善这种疾病的视力丧失。我们认为，计划中的项目具有高度创新性，因为它将建立一种新的实验方法来了解增殖性视网膜病变，并通过揭示以前未知的病理生理机制，将显着改变目前对这种威胁视力的疾病的看法。 从长远来看，阐明增殖性视网膜病变如何对视网膜细胞产生功能改变作用， 视网膜内血管系统可能为治疗这种可怕的并发症提供新的药理学靶点。