Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists

VEGFR 肽模拟拮抗剂对血管生成的靶向调节

基本信息

批准号：
8078085
负责人：
RENATA PASQUALINI
金额：
$ 37.35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8078085
关键词：
Adult Affect Age related macular degeneration Agonist Angiogenesis Inhibitors Animal Model Apoptosis Inhibitor Arthritis Asthma Bacteriophages Binding Biological Assay Blindness Blood Vessels Chemicals Chemotherapy-Oncologic Procedure Cirrhosis Databases Development Diabetes Mellitus Diabetic Retinopathy Diagnosis Disease Drug Delivery Systems Embryonic Development Endothelial Cells Experimental Models Family Female Generations Genes Goals Grant Growth Health Human In Vitro Ligand Binding Ligands Literature Macular degeneration Malignant Neoplasms Mediating Methods Modeling Molecular Mus Neural Retina Neuropilin-1 New Agents Nutrient Obesity Organ Oxygen Pathologic Neovascularization Pathway interactions Peptide Receptor Peptide Transport Peptides Phage Display Pharmaceutical Preparations Process Retina Retinal Retinal Diseases Retinopathy of Prematurity Role Screening procedure Series Testing Therapeutic Time Tissues Toxin Treatment Protocols United States Food and Drug Administration Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Wound Healing angiogenesis antiangiogenesis therapy base cancer therapy design design and construction drug candidate expectation in vivo insight molecular marker mouse model novel peptidomimetics prevent prototype receptor reproductive retina blood vessel structure retinal angiogenesis tumor

项目摘要

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.

描述（由申请人提供）：尽管近乎全面的怀疑主义最初向Folkman提出了他对抗血管生成的看法，即抗血管生成将是一种有效的癌症化疗方法，但该概念现在已被广泛接受，不仅构成了癌症治疗的基础，不仅是癌症治疗的基础，而且还用于对非封存的范围进行广泛的范围，该范围众多的习惯是及时习惯的既定范围，既既依赖又有符合的范围。目前，针对与血管生成有关的中心化学物质的批准疗法是有用的，但不是完全安全或有效的。我们建议通过强大的噬菌体显示方法发现新的抗VEGF代理，并将这些新药物作为即将产生的安全有效的血管生成抑制剂。我们的具体目的是：（i）发现和开发针对VEGF受体家族的新的抗血管生成肽型化合物，以及（ii）设计和测试新的药物以控制视网膜血管生成。这些药物都将有选择地与病理新血管结合并阻止或破坏它们，而不会影响正常的血管。我们的目标是理解和抑制引起人失明疾病的实验小鼠模型的神经视网膜病理性血管生成。公共卫生相关性：这项研究将及时推断出两种负责美国和世界各地的两种主要视网膜血管疾病的治疗，诊断和治疗，为此，我们具有良好的实验模型 - 早产和与年龄相关的黄斑变性的视网膜病变。血管是至关重要的身体成分，可为几乎所有的器官和组织提供氧气和养分。大多数血管在胚胎发育过程中形成，在成年人中，新血管的形成（一种称为血管生成的过程）受到限制，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的形成时才能进展。癌症，肥胖，糖尿病，哮喘，关节炎，肝硬化和眼部疾病是可能因血管生成抑制剂发展而减慢或阻止的众多疾病之一。该提案中的我们的目标是在避免正常血管生成的同时了解和预防视网膜疾病的病理血管生成过程，并期望结果，结果将及时推断到新的视网膜血管疾病的新治疗方案和两种主要视网膜血管疾病的治疗，这使我们在美国具有良好的实验性模型和年龄较高的效果 - 良好的味道 - 预先症状 - 预先症状效果。