Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists

描述（由申请人提供）：尽管Folkman提出的抗血管生成将是癌症化疗的有效方法这一观点最初受到了几乎普遍的怀疑，但这一概念现在已被广泛接受，不仅为癌症治疗奠定了基础，而且为Folkman总结为“血管生成依赖性疾病”的一系列非肿瘤性疾病的治疗奠定了基础。目前批准的针对血管生成过程中涉及的主要身体化学物质VEGF的疗法是有用的，但并非完全安全或有效。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新一代安全有效的血管生成抑制剂应用。我们的具体目标是：(1)发现和开发新的针对VEGF受体家族的抗血管生成类肽化合物，(2)设计和测试用于视网膜血管生成治疗控制的新药物。这些药物可以选择性地结合病理新生血管并阻断或破坏它们，而不影响正常血管。我们的目标是了解和抑制人类致盲疾病实验小鼠模型神经视网膜中的病理性血管生成。公共卫生相关性：本研究将及时推断出在美国和全世界导致失明的两种主要视网膜血管疾病的治疗、诊断和治疗，我们已经有了很好的实验模型——早产儿视网膜病变和年龄相关性黄斑变性。血管是人体必不可少的组成部分，它向几乎所有器官和组织输送氧气和营养。大多数血管是在胚胎发育期间形成的，而在成人中，新血管的形成（一种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，因为一些疾病只有在诱导新血管形成时才会进展；癌症、肥胖、糖尿病、哮喘、关节炎、肝硬化和眼部疾病都可能因血管生成抑制剂的发展而减缓或阻断。我们的目标是在保留正常血管生成的情况下，了解和预防视网膜疾病实验模型中的病理性血管生成过程，期望这些结果能够及时推断出美国两种主要的导致失明的视网膜血管疾病的新的治疗方案和治疗方法，我们已经有了很好的实验模型-早产儿视网膜病变和年龄相关性黄斑变性。

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.