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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：
8268448
负责人：
MICHAEL SEAN ROGERS
金额：
$ 44.35万
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 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8268448
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

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. 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.).

在发达国家，血管生成依赖性疾病是导致失明的主要原因

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Galloyl Carbohydrates with Antiangiogenic Activity Mediated by Capillary Morphogenesis Gene 2 (CMG2) Protein Binding.

没食子酰碳水化合物具有由毛细血管形态发生基因 2 (CMG2) 蛋白结合介导的抗血管生成活性。

DOI：
10.1021/acs.jmedchem.8b01988
发表时间：
2019
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
G-Doyagüez,Elisa;Carrero,Paula;Madrona,Andrés;Rodriguez-Salamanca,Patricia;Martínez-Gualda,Belén;Camarasa,MaríaJosé;Jimeno,MaríaLuisa;Bennallack,PhilipR;Finnell,JordanG;Tsang,Tsz-Ming;Christensen,KennethA;San-Félix,Ana;Rogers,
通讯作者：
Rogers,

1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2.

DOI：
10.1021/jm301558t
发表时间：
2013-03-14
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Cryan, Lorna M.;Bazinet, Lauren;Habeshian, Kaiane A.;Cao, Shugeng;Clardy, Jon;Christensen, Kenneth A.;Rogers, Michael S.
通讯作者：
Rogers, Michael S.

A FRET-based high throughput screening assay to identify inhibitors of anthrax protective antigen binding to capillary morphogenesis gene 2 protein.

DOI：
10.1371/journal.pone.0039911
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Rogers MS;Cryan LM;Habeshian KA;Bazinet L;Caldwell TP;Ackroyd PC;Christensen KA
通讯作者：
Christensen KA

Targeting the anthrax receptors, TEM-8 and CMG-2, for anti-angiogenic therapy.

DOI：
10.2741/3806
发表时间：
2011-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
0
作者：
Cryan LM;Rogers MS
通讯作者：
Rogers MS

Spontaneous reversion of the angiogenic phenotype to a nonangiogenic and dormant state in human tumors.

人类肿瘤中血管生成表型自发回复为非血管生成和休眠状态。

DOI：
10.1158/1541-7786.mcr-13-0532-t
发表时间：
2014
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Rogers,MichaelS;Novak,Katherine;Zurakowski,David;Cryan,LornaM;Blois,Anna;Lifshits,Eugene;Bø,TrondH;Oyan,AnneM;Bender,EliseR;Lampa,Michael;Kang,Soo-Young;Naxerova,Kamila;Kalland,Karl-Henning;Straume,Oddbjorn;Akslen,LarsA;
通讯作者：