Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors

血管生成依赖性疾病是发达国家失明的一个主要原因，在那里 仍然是广泛有效的抗血管生成疗法的普遍突出需求，这种疗法不会抑制 一个单一的增长因素。我们发现炭疽保护性抗原突变体(例如PASSSR)可以 有效抑制多种生长因子诱导的角膜新生血管形成。我们的长期目标是 了解这种抑制的机制，并开发适当的治疗方法 基于这一机制。我们的工作假设是内源性配体(S)与炭疽病的结合 毒素受体(ANTXR1/TEM8和/或ANTXR2/CMG2)在血管生成过程中起重要作用 相互竞争的配体抑制这种相互作用将抑制血管生成。我们将采用几种策略来 检验这一假设。首先，我们将解释导致观察到的 PASSSR的抗血管生成活性。我们将最终确定介导这一过程的特异性受体(S) PASSSR及与此作用相关的信号分子S可抑制其抗血管生成作用。第二，我们 将鉴定小分子ATR抑制剂并评估其体外抗血管生成性能。相关小规模 分子抑制剂将使用作为NIH一部分开发的高通量筛选试验来分离 路线图倡议。识别出的分子的抗血管生成活性将在组织中进行评估。 文化。第三，我们将评估分离的ATR抑制剂在体内抑制眼血管生成的能力。 抗血管生成活性将使用两种眼血管生成的小鼠模型进行评估：角膜 新生血管模型和激光诱导的脉络膜新生血管模型。成功完成 这两项研究都将炭疽毒素受体(S)确立为抗血管生成治疗的合适靶点 并为广谱抗血管生成治疗提供小分子先导化合物。病理学 这项提案的成功完成将包括眼部血管生成障碍 如黄斑变性、糖尿病视网膜病变、早产儿视网膜病变、青光眼、角膜 与疱疹病毒性角膜炎、沙眼、烧伤和 角膜移植的血运重建，以及其他依赖血管生成的疾病，如癌症，关节炎， 和心血管疾病。因此，这些研究可能会对人类健康产生重大影响。我们已经证明，炭疽毒素受体的大蛋白抑制剂可以抑制角膜 新生血管和其他依赖血管生成的疾病。我们试图通过以下方式了解这一机制 这种抑制作用的发生，并确定具有类似活性的小分子。这些分子或类似分子 分子可用于治疗角膜新生血管和其他依赖血管生成的疾病。 (例如黄斑变性、糖尿病视网膜病变、早产儿视网膜病变、癌症、心血管疾病、 关节炎等)。

Angiogenesis dependant disease is a major cause of blindness in the developed world, and there remains a generalized outstanding need for broadly active antiangiogenesis therapies which do not inhibit just a single growth factor. We have discovered that anthrax protective antigen mutants (e.g. PASSSR) can powerfully suppress corneal neovascularization induced by multiple growth factors. Our long-range goal is to understand the mechanism by which this suppression is accomplished and develop appropriate therapeutics based on this mechanism. Our working hypotheses is that binding of endogenous ligand(s) to the anthrax toxin receptors (ANTXR1/TEM8 and/or ANTXR2/CMG2) is important in angiogenic processes, and that inhibition of this interaction by competing ligands will inhibit angiogenesis. We will employ several strategies to test this hypothesis. First, we will explain the biochemical mechanism responsible for the observed antiangiogenic activity of PASSSR. We will definitively identify both the specific receptor(s) that mediate the antiangiogenic effect inhibited by PASSSR and the signaling molecule(s) associated with that effect. Second, we will identify small molecule ATR inhibitors and assess their antiangiogenic properties ex vivo. Relevant small molecule inhibitors will be isolated using high throughput screening assays developed as a part of the NIH Roadmap Initiative. The antiangiogenic activity of the identified molecules will then be evaluated in tissue culture. Third, we will assess the ability of isolated ATR inhibitors to inhibit ocular angiogenesis in vivo. Antiangiogenic activity will be evaluated using two mouse models of ocular angiogenesis: the corneal neovascularization model, and a laser-induced choroidal neovascularization model. Successful completion of these studies will both establish the anthrax toxin receptor(s) as appropriate targets for antiangiogenic therapy and provide small molecule lead compounds for broad spectrum antiangiogenic therapies. Pathologies addressed by successful completion of this proposal would thus encompass disorders of ocular angiogenesis such as macular degeneration, diabetic retinopathy, retinopathy of prematurity, and glaucoma, corneal neovascularization associated with conditions such as Herpetic Keratitis, Trachoma, burns, and revascularization of corneal transplants, and other angiogenesis-dependant diseases such as cancer, arthritis, and cardiovascular disease. Hence, these studies are likely to have a significant impact on human health. We have shown that large protein inhibitors of the anthrax toxin receptors can inhibit corneal neovascularization and other angiogenesis-dependant diseases. We seek to understand the mechanism by which this inhibition occurs and identify small molecules with similar activity. These molecules, or similar molecules can then be used to treat corneal neovascularization, and other angiogenesis-dependant diseases (e.g. macular degeneration, diabetic retinopathy, retinopathy of prematurity, cancer, cardiovascular disease, arthritis, etc.).