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:
  • 金额:
    $ 44.35万
  • 依托单位:
  • 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

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:
  • 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:
  • 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:
  • 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.
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:
  • 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:
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MICHAEL SEAN ROGERS其他文献

MICHAEL SEAN ROGERS的其他文献

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{{ truncateString('MICHAEL SEAN ROGERS', 18)}}的其他基金

Functional requirement of CMG2 for endothelial cell chemotaxis and resulting angiogenesis
CMG2 内皮细胞趋化性和由此产生的血管生成的功能要求
  • 批准号:
    10522258
  • 财政年份:
    2022
  • 资助金额:
    $ 44.35万
  • 项目类别:
Identification of a Novel Target for the Treatment of Endometriosis-associated Pain
确定治疗子宫内膜异位症相关疼痛的新靶点
  • 批准号:
    10508963
  • 财政年份:
    2022
  • 资助金额:
    $ 44.35万
  • 项目类别:
Identification of a Novel Target for the Treatment of Endometriosis-associated Pain
确定治疗子宫内膜异位症相关疼痛的新靶点
  • 批准号:
    10705085
  • 财政年份:
    2022
  • 资助金额:
    $ 44.35万
  • 项目类别:
Functional requirement of CMG2 for endothelial cell chemotaxis and resulting angiogenesis
CMG2 内皮细胞趋化性和由此产生的血管生成的功能要求
  • 批准号:
    10705632
  • 财政年份:
    2022
  • 资助金额:
    $ 44.35万
  • 项目类别:
CMG2 as a target for safe and effective treatment of endometriosis-associate pain
CMG2 作为安全有效治疗子宫内膜异位症相关疼痛的靶点
  • 批准号:
    10583339
  • 财政年份:
    2022
  • 资助金额:
    $ 44.35万
  • 项目类别:
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
  • 批准号:
    7615664
  • 财政年份:
    2008
  • 资助金额:
    $ 44.35万
  • 项目类别:
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
  • 批准号:
    8068796
  • 财政年份:
    2008
  • 资助金额:
    $ 44.35万
  • 项目类别:
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
  • 批准号:
    8072400
  • 财政年份:
    2008
  • 资助金额:
    $ 44.35万
  • 项目类别:
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
  • 批准号:
    7436075
  • 财政年份:
    2008
  • 资助金额:
    $ 44.35万
  • 项目类别:
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
  • 批准号:
    7813810
  • 财政年份:
    2008
  • 资助金额:
    $ 44.35万
  • 项目类别:

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