Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists

描述（由申请人提供）：尽管最初对Folkman提出的抗血管生成将是癌症化疗的有效方法的想法几乎普遍持怀疑态度，但这一概念现在已被广泛接受，不仅形成了癌症治疗的基础，而且还形成了Folkman在术语“血管生成依赖性疾病”下总结的广泛的非肿瘤性疾病的治疗基础。目前批准的针对参与血管生成的中心身体化学物质VEGF的疗法是有用的，但并不完全安全或有效。我们建议通过强大的噬菌体展示方法开发新的抗VEGF药物，并将这些新药物作为下一代安全有效的血管生成抑制剂。我们的具体目标是：（i）发现和开发靶向VEGF受体家族的新的抗血管生成肽模拟物化合物，和（ii）设计和测试用于治疗性控制视网膜血管生成的新试剂。这两种药物都能选择性地与病理性新血管结合，并阻断或破坏它们，而不影响正常血管。我们的目标是了解和抑制病理性血管生成的实验小鼠模型的人类致盲性疾病的神经视网膜。公共卫生相关性：这项研究将及时外推到美国和全世界两种主要视网膜血管疾病的治疗，诊断和治疗，这两种疾病是导致失明的原因，我们有很好的实验模型-早产儿视网膜病变和年龄相关性黄斑变性。血管是身体的重要组成部分，它将氧气和营养物质输送到几乎所有的器官和组织。大多数血管是在胚胎发育过程中形成的，而在成年人中，新血管的形成（一个称为血管生成的过程）是有限的，主要是在伤口愈合和正常的女性生殖周期期间。这为治疗创造了机会，因为几种疾病只有在诱导新血管形成时才能进展;癌症，肥胖症，糖尿病，哮喘，关节炎，肝硬化和眼部疾病是许多疾病中可能被血管生成抑制剂的发展减缓或阻断的疾病。我们的目标是在视网膜疾病的实验模型中理解和预防病理性血管生成过程，同时保留正常的血管生成，期望结果将及时，外推到新的治疗方案和治疗两个主要的视网膜血管疾病导致失明在美国，我们有很好的实验模型-早产儿视网膜病变和年龄，黄斑变性

DESCRIPTION (provided by applicant): Despite the near-universal skepticism that initially greeted Folkman's presentation of his idea that anti-angiogenesis would be an effective approach to cancer chemotherapy, this concept has now become widely accepted and forms a basis not only for cancer therapy, but also for therapy of a broad range of non-neoplastic disorders that Folkman summarizes under the term 'angiogenesis-dependent diseases'. Currently approved therapies, directed against the central bodily chemical involved in angiogenesis, VEGF, are useful, but not entirely safe or effective. We propose to develop new anti-VEGF agents through discovery by powerful phage display methods, and to apply these new agents as a forthcoming generation of safe and effective angiogenesis inhibitors. Our specific aims are: (i) to discover and develop new anti-angiogenic peptidomimetic compounds targeting the VEGF receptor family, and (ii) to design and test new agents for therapeutic control of retinal angiogenesis. These agents would both bind selectively to pathological new blood vessels and block or destroy them, without affecting normal blood vessels. Our goal is to understand and inhibit pathological angiogenesis in the neural retina of experimental mouse models of human blindness-causing diseases. PUBLIC HEALTH RELEVANCE:This study will, in time, extrapolate to treatment, diagnosis and therapy of two major retinal vascular diseases responsible for blindness in the U.S. and throughout the world, for which we have good experimental models - retinopathy of prematurity and age-related macular degeneration. Blood vessels are essential bodily components that deliver oxygen and nutrients to almost all organs and tissues. Most vessels are formed during embryonic development, and in adults the formation of new blood vessels (a process called angiogenesis) is limited, mainly during wound healing and the normal female reproductive cycle. This creates an opportunity for therapy, as several diseases can progress only if they induce the formation of new blood vessels; cancer, obesity, diabetes, asthma, arthritis, cirrhosis, and ocular diseases are among the many illnesses likely to be slowed down or blocked by the development of angiogenesis inhibitors. Our goal in this proposal is to understand and prevent the pathological angiogenesis process in experimental models for diseases of the retina while sparing normal angiogenesis, with the expectation that the results will, in time, extrapolate to new treatment regimens and therapy for the two major retinal vascular diseases causing blindness in the U.S. for which we have good experimental models - retinopathy of prematurity and age-related macular degeneration.