Retinovascular pathophysiology: focus on proliferative retinopathy

描述（由申请人提供）：本研究将采用一种新颖的实验策略来加深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一种视力威胁并发症。尽管激光和抗vegf治疗有好处，但这种并发症仍会导致失明。目前，针对增殖性视网膜病变问题的新治疗方法的发展受到其病理生理学知识差距的限制。为了更好地理解以视网膜表面异常新生血管生长为特征的增殖性视网膜病变的病理生理学，我们假设视网膜前新生血管对视网膜内血管系统起功能改变作用。通过引起血管功能障碍，从而损害局部灌注以满足代谢需求的有效调节，这种新假设的病理生理机制可能加剧视网膜缺氧，从而有力地刺激新生血管。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，我们利用一种成熟的增殖性视网膜病变小鼠模型进行了初步研究。基于我们广泛使用膜片钳技术来阐明视网膜脉管系统的功能组织，我们的初步研究提供了病理的第一个电生理评估

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.