Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists

描述(申请人提供)：尽管Folkman最初提出的抗血管生成将是癌症化疗的有效方法的想法受到了几乎所有人的怀疑，但这一概念现在已被广泛接受，不仅构成了癌症治疗的基础，而且还构成了Folkman总结的一系列非肿瘤性疾病的治疗基础，Folkman将其概括为“血管生成依赖型疾病”。目前批准的针对参与血管生成的中枢身体化学物质血管内皮生长因子的疗法是有用的，但并不完全安全或有效。我们建议通过发现有效的噬菌体展示方法来开发新的抗血管内皮生长因子药物，并将这些新药物应用于下一代安全有效的血管生成抑制剂。我们的具体目标是：(I)发现和开发新的以血管内皮生长因子受体家族为靶点的抗血管生成多肽化合物，以及(Ii)设计和测试用于视网膜血管生成治疗控制的新药物。这些药物都会选择性地与病理性的新血管结合，并阻断或摧毁它们，而不会影响正常的血管。我们的目标是了解和抑制人类致盲疾病的实验性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：这项研究将及时推断出美国和世界各地导致失明的两种主要视网膜血管疾病的治疗、诊断和治疗，对于这两种疾病，我们有很好的实验模型-早产儿视网膜病变和老年性黄斑变性。血管是人体的基本组成部分，向几乎所有器官和组织输送氧气和营养物质。大多数血管是在胚胎发育期间形成的，而成年人新血管的形成(称为血管生成)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的情况下才能进展；癌症、肥胖症、糖尿病、哮喘、关节炎、肝硬变和眼疾等许多疾病可能会被血管生成抑制剂的开发减缓或阻止。我们在这项建议中的目标是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，同时保留正常的血管生成，期望结果将及时推断出新的治疗方案和治疗在美国导致失明的两种主要视网膜血管疾病-早产儿视网膜病变和老年性黄斑变性。

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.