ADENOSINE RECEPTORS TO INHIBIT RETINAL ANGIOGENESIS

视网膜微血管异常，如早产儿视网膜病变、黄斑变性和糖尿病视网膜病变是导致非外伤性失明的主要原因。这些疾病的特点是由于视网膜血管的缺血性损伤而导致的新生血管，即代偿性血管生成。在低氧诱导视网膜新生血管的小鼠模型中，我们计划确定核苷腺苷在代偿性血管生成中的作用。为了量化细胞增殖和新生血管的程度，我们将使用细胞化学和数字形态计量学。腺苷由缺氧或受损的组织释放增加，已被证明是血管生成的强有力的促进剂。我们计划检验以下假设：视网膜缺血所释放的腺苷会在内皮细胞中产生增殖效应，由此产生的代偿性血管生成应该被腺苷受体拮抗剂阻止或减少。因此，使用腺苷受体拮抗剂阻断将通过阻断腺苷的作用来抑制视网膜新生血管。综上所述，在这个项目的第一阶段，我们将确定腺苷受体的激活是否在视网膜循环的代偿性血管生成的发展中发挥机制作用。如果我们的假设被证明是正确的，这个视网膜病变的小动物模型将被用于该项目的第二阶段：(A)确定介导血管生成的腺苷受体亚型(例如，A2A或A2B)，以及(B)评估用于治疗的新型腺苷受体拮抗剂的作用。该项目的成功完成将导致一种新的战略，以对抗与视网膜新生血管相关的视网膜病理。建议的商业应用：我们的建议将建立内源性释放的腺苷，通过腺苷受体作用，与视网膜新生血管之间的因果关系。视网膜新生血管是糖尿病视网膜病变、早产儿视网膜病变和老年性黄斑变性的主要原因。我们的目的是发现、开发和商业化腺苷拮抗剂(针对特定受体亚型，例如A2B)，以减缓或防止视网膜新生血管。

Microvascular abnormalities of the retina, such as retinopathy of prematurity, macular degeneration and diabetic retinopathy are among the leading causes of non-traumatic blindness. These diseases are characterized by neovascularization that results from ischemic injury to retinal vessels, i.e., compensatory angiogenesis. In a mouse pup model of hypoxia-induced neovascularization of the retina, we plan to determine the role of the nucleoside adenosine in the compensatory angiogenesis. To quantify cell proliferation and the degree of neovascularization we will use cytochemistry and digital morphometry. Adenosine is released in increased amounts by hypoxic or damaged tissues, and has been shown to be a potent promoter of angiogenesis. We plan to test the following hypothesis: Adenosine released as a result of retinal ischemia produces proliferative effects in endothelial cells, and the resultant compensatory angiogenesis should be prevented or reduced by adenosine receptor antagonists. Thus, blocking using adenosine receptor antagonists will inhibit retinal neovascularization by blocking the effect of adenosine. In summary in the first phase of this project we will determine whether activation of adenosine receptors plays a mechanistic role in the development of compensatory angiogenesis of the retinal circulation. If our hypothesis is proven correct this small animal model of retinopathy will be used on the second phase of this project to (A) determine the adenosine receptors subtype that (e.g., A2A or A2B) that mediates angiogenesis, and (B) evaluate the action of novel adenosine receptor antagonists for therapeutic use. Successful accomplishment of this project will lead to a novel strategy to combat retinal pathologies associated with retinal neovascularization. PROPOSED COMMERCIAL APPLICATION: Our proposal will establish a causal relationship between endogenously released adenosine, acting via an adenosine receptor, and retinal neovascularization. Retinal neovascularization is the primary cause of diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. It is our intention to discover, develop, and commercialize an antagonist of adenosine (targeted to a specific receptor subtype, e.g., A2B) to slow or prevent retinal neovascularization.