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Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors

针对炭疽毒素受体的新型血管生成抑制剂

基本信息

批准号：
8068796
负责人：
MICHAEL SEAN ROGERS
金额：
$ 41.47万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068796
关键词：
Address Affinity Amino Acids Angiogenesis Inhibitors Anthrax disease Antigens Arthritis Binding Biochemical Biological Assay Biological Process Blindness Blood Vessels Blood capillaries Boston Burn injury Cardiovascular Diseases Cells Choroidal Neovascularization Clinical Trials Collaborations Complex Corneal Neovascularization Data Development Diabetic Retinopathy Disease Emerging Communicable Diseases Endothelial Cells Exhibits Extracellular Matrix Eye diseases FDA approved Fibroblast Growth Factor 2 Fluorescence Resonance Energy Transfer Gene Proteins Generations Glaucoma Goals Growth Growth Factor Health Herpetic Keratitis Human Immunoglobulin Fragments In Vitro Individual Infection Investigation Keratoplasty Laboratories Lasers Lead Ligands Lucentis Macular degeneration Malignant Neoplasms Mediating Modeling Morphogenesis Neovascular Glaucoma Outcome Panzem Pathology Pathway interactions Patients Pharmaceutical Chemistry Pharmacotherapy Process Property Proteins Research Retinopathy of Prematurity Revlimid Role Screening procedure Series Signal Pathway Signal Transduction Signaling Molecule Source Testing Thalidomide Therapeutic Toxic effect Trachoma United States National Institutes of Health Validation Vascular Endothelial Growth Factors Vision Work angiogenesis anthrax protective factor anthrax toxin anthrax toxin receptors antiangiogenesis therapy base bevacizumab biodefense capillary design effective therapy experience high throughput screening improved in vivo inhibitor/antagonist innovation member migration mouse model mutant novel ocular angiogenesis pre-clinical receptor receptor binding skills small molecule tissue culture tumor endothelial marker 8 tumor growth

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis dependant disease is a major cause of blindness in the developed world, and there remains a generalized outstanding need for broadly active antiangiogenesis therapies which do not inhibit just a single growth factor. We have discovered that anthrax protective antigen mutants (e.g. PASSSR) can powerfully suppress corneal neovascularization induced by multiple growth factors. Our long-range goal is to understand the mechanism by which this suppression is accomplished and develop appropriate therapeutics based on this mechanism. Our working hypotheses is that binding of endogenous ligand(s) to the anthrax toxin receptors (ANTXR1/TEM8 and/or ANTXR2/CMG2) is important in angiogenic processes, and that inhibition of this interaction by competing ligands will inhibit angiogenesis. We will employ several strategies to test this hypothesis. First, we will explain the biochemical mechanism responsible for the observed antiangiogenic activity of PASSSR. We will definitively identify both the specific receptor(s) that mediate the antiangiogenic effect inhibited by PASSSR and the signaling molecule(s) associated with that effect. Second, we will identify small molecule ATR inhibitors and assess their antiangiogenic properties ex vivo. Relevant small molecule inhibitors will be isolated using high throughput screening assays developed as a part of the NIH Roadmap Initiative. The antiangiogenic activity of the identified molecules will then be evaluated in tissue culture. Third, we will assess the ability of isolated ATR inhibitors to inhibit ocular angiogenesis in vivo. Antiangiogenic activity will be evaluated using two mouse models of ocular angiogenesis: the corneal neovascularization model, and a laser-induced choroidal neovascularization model. Successful completion of these studies will both establish the anthrax toxin receptor(s) as appropriate targets for antiangiogenic therapy and provide small molecule lead compounds for broad spectrum antiangiogenic therapies. Pathologies addressed by successful completion of this proposal would thus encompass disorders of ocular angiogenesis such as macular degeneration, diabetic retinopathy, retinopathy of prematurity, and glaucoma, corneal neovascularization associated with conditions such as Herpetic Keratitis, Trachoma, burns, and revascularization of corneal transplants, and other angiogenesis-dependant diseases such as cancer, arthritis, and cardiovascular disease. Hence, these studies are likely to have a significant impact on human health. PUBLIC HEALTH RELEVANCE. We have shown that large protein inhibitors of the anthrax toxin receptors can inhibit corneal neovascularization and other angiogenesis-dependant diseases. We seek to understand the mechanism by which this inhibition occurs and identify small molecules with similar activity. These molecules, or similar molecules can then be used to treat corneal neovascularization, and other angiogenesis-dependant diseases (e.g. macular degeneration, diabetic retinopathy, retinopathy of prematurity, cancer, cardiovascular disease, arthritis, etc.).

描述（由申请人提供）：血管生成依赖性疾病是发达国家致盲的主要原因，对不抑制单一生长因子的广泛性抗血管生成治疗仍有普遍的突出需求。我们发现炭疽保护抗原突变体（如PASSSR）可以有效抑制多种生长因子诱导的角膜新生血管。我们的长期目标是了解这种抑制实现的机制，并基于这种机制开发适当的治疗方法。我们的工作假设是内源性配体与炭疽毒素受体（ANTXR1/TEM8和/或ANTXR2/CMG2）的结合在血管生成过程中是重要的，并且竞争配体抑制这种相互作用将抑制血管生成。我们将采用几种策略来检验这一假设。首先，我们将解释PASSSR抗血管生成活性的生化机制。我们将明确确定介导PASSSR抑制的抗血管生成作用的特定受体和与该作用相关的信号分子。其次，我们将鉴定小分子ATR抑制剂并评估其体外抗血管生成特性。相关的小分子抑制剂将使用作为NIH路线图倡议的一部分开发的高通量筛选测定法进行分离。鉴定出的分子的抗血管生成活性将在组织培养中进行评估。第三，我们将评估分离ATR抑制剂在体内抑制眼血管生成的能力。我们将利用角膜新生血管模型和激光诱导脉络膜新生血管模型两种小鼠眼部血管生成模型来评估抗血管生成活性。这些研究的成功完成将确立炭疽毒素受体作为抗血管生成治疗的合适靶点，并为广谱抗血管生成治疗提供小分子先导化合物。因此，成功完成本提案所涉及的病理将包括眼部血管生成疾病，如黄斑变性、糖尿病视网膜病变、早产儿视网膜病变和青光眼，与疱疹性角膜炎、沙眼、烧伤和角膜移植血管重建等疾病相关的角膜新生血管形成，以及其他血管生成依赖疾病，如癌症、关节炎和心血管疾病。因此，这些研究可能对人类健康产生重大影响。公共卫生相关性。我们已经证明炭疽毒素受体的大蛋白抑制剂可以抑制角膜新生血管和其他血管生成依赖性疾病。我们试图了解这种抑制发生的机制，并识别具有类似活性的小分子。这些分子或类似分子可用于治疗角膜新生血管和其他依赖血管生成的疾病（如黄斑变性、糖尿病视网膜病变、早产儿视网膜病变、癌症、心血管疾病、关节炎等）。