ADENOSINE RECEPTORS TO INHIBIT RETINAL ANGIOGENESIS

视网膜微血管异常，例如早产儿视网膜病变、黄斑变性和糖尿病性视网膜病变，是非外伤性失明的主要原因。 这些疾病的特征是由视网膜血管缺血性损伤引起的新血管形成，即代偿性血管生成。 在缺氧诱导的视网膜新生血管形成的小鼠幼崽模型中，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血管形成的程度，我们将使用细胞化学和数字形态测定法。 缺氧或受损的组织会释放更多的腺苷，并已被证明是血管生成的有效促进剂。 我们计划检验以下假设：由于视网膜缺血而释放的腺苷对内皮细胞产生增殖作用，并且腺苷受体拮抗剂应预防或减少由此产生的代偿性血管生成。 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形成。 总之，在该项目的第一阶段，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，该视网膜病小动物模型将用于该项目的第二阶段，以（A）确定介导血管生成的腺苷受体亚型（例如A2A或A2B），以及（B）评估新型腺苷受体拮抗剂的治疗用途。 该项目的成功完成将产生一种新的策略来对抗与视网膜新生血管形成相关的视网膜病变。拟议的商业应用：我们的提案将建立通过腺苷受体作用的内源性释放的腺苷与视网膜新生血管形成之间的因果关系。 视网膜新生血管形成是糖尿病性视网膜病变、早产儿视网膜病变和年龄相关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），以减缓或预防视网膜新生血管形成。

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.