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失明的主要原因，并且对于不仅仅抑制单一生长因子的广泛活性的抗血管生成疗法仍然存在普遍的突出需求。我们发现炭疽保护性抗原突变体（例如PASSSR）可以有效抑制多种生长因子诱导的角膜新生血管形成。我们的长期目标是了解实现这种抑制的机制，并根据该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很重要，并且通过竞争性配体抑制这种相互作用将抑制血管生成。我们将采用多种策略来检验这个假设。首先，我们将解释观察到的 PASSSR 抗血管生成活性的生化机制。我们将明确鉴定介导 PASSSR 抑制的抗血管生成作用的特定受体以及与该作用相关的信号分子。其次，我们将鉴定小分子 ATR 抑制剂并评估其离体抗血管生成特性。将使用作为 NIH 路线图计划的一部分开发的高通量筛选测定法来分离相关的小分子抑制剂。然后将在组织培养中评估所鉴定分子的抗血管生成活性。第三，我们将评估分离的 ATR 抑制剂在体内抑制眼部血管生成的能力。将使用两种眼血管生成小鼠模型来评估抗血管生成活性：角膜新生血管模型和激光诱导脉络膜新生血管模型。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适当靶标，并为广谱抗血管生成治疗提供小分子先导化合物。因此，成功完成该提案所解决的病理学将包括眼部血管生成疾病，例如黄斑变性、糖尿病性视网膜病、早产儿视网膜病和青光眼，与疱疹性角膜炎、沙眼、烧伤和角膜移植血运重建等病症相关的角膜新生血管形成，以及其他血管生成依赖性疾病，例如癌症、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形成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。这些分子或类似的分子然后可用于治疗角膜新血管形成和其他血管生成依赖性疾病(例如黄斑变性、糖尿病性视网膜病、早产儿视网膜病、癌症、心血管疾病、关节炎等)。