Retinovascular pathophysiology: focus on proliferative retinopathy

描述(申请人提供)：拟议的研究将使用一种新的实验策略来加强我们对增殖性视网膜病变的病理生理学的了解，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威胁视力的并发症。尽管激光和抗血管内皮生长因子治疗有好处，但这种并发症仍然导致失明。目前，增殖性视网膜病变的新治疗方法的发展受到其病理生理学知识空白的限制。为了更好地了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的作用。通过导致血管功能障碍，从而影响局部血流灌注的有效调节以满足代谢需求，这种新的病理生理机制可能会加剧视网膜缺氧，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，我们利用一个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来阐明视网膜血管系统的功能组织的基础上，我们的初步研究提供了第一个病理的电生理学评估 任何纸巾里都有新生血管。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从视网膜前新生血管传递的超极化电压驱动到高的功能改变水平，以及(2)增殖性视网膜病变从根本上改变了视网膜血管对缺氧驱动的血管活性信号腺苷的反应。实现这些特定的目标将为增殖性视网膜病变的病理生理学开辟一条全新的科学探索路线。此外，建议的 研究将创造新的知识，可能有助于开发一种新的治疗策略来改善这种疾病的视力损失。在我们看来，计划中的项目具有很高的创新性，因为它将为理解增殖性视网膜病变建立一种新的实验方法，并通过揭示以前未知的病理生理机制，将显著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在 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靶点。

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.