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，并且对广泛活跃的抗血管生成疗法仍然存在普遍的杰出需求，这些疗法并不仅仅抑制单个生长因子。我们已经发现，炭疽保护性抗原突变体（例如PassSR）可以强大地抑制由多种生长因子诱导的角膜新生血管形成。我们的远程目标是了解实现这种抑制并根据该机制开发适当的治疗剂的机制。我们的工作假设是，内源配体（S）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，并且通过竞争配体抑制这种相互作用将抑制这种相互作用。我们将采用几种策略来检验这一假设。首先，我们将解释导致PASSSR观察到的抗血管生成活性的生化机制。我们将确定识别介导PASSR抑制的抗血管生成效应的特定受体和与该作用相关的信号分子（S）。其次，我们将鉴定出小分子ATR抑制剂，并在体内评估其抗血管生成特性。相关的小分子抑制剂将使用作为NIH路线图计划的一部分开发的高吞吐量筛选测定法分离出来。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血管生成的能力。抗血管生成活性将使用两种小鼠眼血管生成的模型进行评估：角膜新生血管化模型和激光诱导的脉络膜新生血管形成模型。这些研究的成功完成都将建立炭疽毒素受体作为抗血管生成疗法的适当靶标，并为广谱抗血管生成疗法提供小分子铅化合物。通过成功完成该提案来解决的病理学将涵盖眼部血管生成的疾病，例如黄斑变性，糖尿病性视网膜病变，早产性视网膜病和青光眼，与疱疹性角膜炎，三神经膜，脑膜炎，烧伤和其他cornereal cornereal cornereal cornereal cornereal cornereal corniale contripia controsia controsia corniale corniale corniale corniale contripia和其他相关的条件相关的角膜新生血管化，以及其他疾病。关节炎和心血管疾病。因此，这些研究可能会对人类健康产生重大影响。公共卫生相关性。我们已经表明，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依赖血管生成的疾病。我们试图了解这种抑制作用的机制并鉴定具有相似活性的小分子。然后可以使用这些分子或类似的分子来治疗角膜新生血管形成，以及其他依赖血管生成依赖性疾病（例如黄斑退化，糖尿病性视网膜病，早产，癌症，心血管疾病，心血管疾病，关节炎等）。