ADENOSINE RECEPTORS TO INHIBIT RETINAL ANGIOGENESIS

腺苷受体抑制视网膜血管生成

• 批准号: 6073941
• 负责人: LUIZ BELARDINELLI
• 金额: $ 11.83万
• 依托单位: CV THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6073941
• 关键词: adenosine; angiogenesis; angiogenesis inhibitors; drug screening /evaluation; eye agent; eye disorder chemotherapy; laboratory mouse; proliferative vitreoretinopathy; purinergic receptor; retina circulation; retinopathy of prematurity; vascular endothelial growth factors

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.

视网膜的微血管异常，如早产儿视网膜病变、黄斑变性和糖尿病视网膜病变是非创伤性失明的主要原因。 这些疾病的特征在于由视网膜血管的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的小鼠幼鼠模型中，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形成的程度，我们将使用细胞化学和数字形态测量。 腺苷在缺氧或受损组织中的释放量增加，并且已被证明是血管生成的有效促进剂。 我们计划测试以下假设：由于视网膜缺血而释放的腺苷在内皮细胞中产生增殖作用，并且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形成。 总之，在本项目的第一阶段，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起机械作用。 如果我们的假设被证明是正确的，则该视网膜病的小动物模型将用于该项目的第二阶段，以（A）确定腺苷受体亚型（例如，A2 A或A2 B）介导血管生成，和（B）评价用于治疗用途的新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策略，以打击视网膜新生血管相关的视网膜病变。拟定商业应用：我们的建议将建立内源性释放的腺苷，通过腺苷受体，和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（靶向特定受体亚型，例如，A2B）减缓或预防视网膜新生血管形成。