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：
7844829
负责人：
RENATA PASQUALINI
金额：
$ 38.91万
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/7844829
关键词：
Adult Affect Age related macular degeneration Agonist Angiogenesis Inhibitors Animal Model Apoptosis Inhibitor Arthritis Asthma Bacteriophages Binding 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 Hand Human Ligand Binding Ligands Literature Macular degeneration Malignant Neoplasms 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 insight mouse model neoplastic novel peptidomimetics prevent prototype public health relevance 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）：尽管福克曼提出抗血管生成将是癌症化疗的有效方法的想法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，并且不仅成为癌症治疗的基础，而且还用于治疗多种非肿瘤性疾病，福克曼将其总结为“血管生成依赖性疾病”。目前批准的疗法针对参与血管生成的中心身体化学物质 VEGF，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发现来开发新的抗 VEGF 药物，并将这些新药物用作下一代安全有效的血管生成抑制剂。我们的具体目标是：(i) 发现和开发针对 VEGF 受体家族的新型抗血管生成拟肽化合物，以及 (ii) 设计和测试用于治疗控制视网膜血管生成的新药物。这些药物都会选择性地与病理性新血管结合并阻塞或破坏它们，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。公共健康相关性：这项研究将及时推断出导致美国和全世界失明的两种主要视网膜血管疾病的治疗、诊断和治疗，对此我们拥有良好的实验模型 - 早产儿视网膜病变和年龄相关性视网膜病变黄斑变性。血管是向几乎所有器官和组织输送氧气和营养物质的重要身体组成部分。大多数血管是在胚胎发育过程中形成的，而在成人中，新血管的形成（称为血管生成的过程）是有限的，主要是在伤口愈合和正常女性生殖周期期间。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、肝硬化和眼部疾病等许多疾病可能会因血管生成抑制剂的发展而减缓或阻止。我们本提案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，期望结果能够及时推断出新的治疗方案和两种主要视网膜疾病的治疗方法。在美国，我们有良好的实验模型来治疗导致失明的血管疾病——早产儿视网膜病变和年龄相关性黄斑变性。