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INTEGRIN ASSOCIATED PROTEIN/CD47 IS A THROMBOSPONDIN RECEPTOR

整合素相关蛋白/CD47 是一种血小板反应蛋白受体

基本信息

批准号：
8288113
负责人：
WILLIAM A FRAZIER
金额：
$ 37.62万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288113
关键词：
Address Affect Affinity Avidity Binding Binding Sites Biological Assay Blood Platelets Blood Vessels Bone Marrow Bone Resorption C-terminal CD36 Antigens CD36 gene CD47 Antigen CD47 gene Cardiovascular Diseases Cardiovascular system Cells Cholesterol Complex Crystallization Cultured Cells Cyclic GMP Electron Microscopy Elements Fostering Grant Health Homologous Gene Hyperplasia Injury Integrin Binding Integrins Ischemia Knockout Mice Lateral Leukocytes Ligands Membrane Methods Modeling Molecular Monitor Mus Mutagenesis Mutation Necrosis Nitric Oxide Osteoclasts Oxygen Peptides Perfusion Phenotype Physiological Platelet Activation Play Process Property Proteins Regulation Resistance Role Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Structure Sum Surface Testing Thrombospondin 1 Time Tissues Transgenes Vascular System X ray diffraction analysis X-Ray Crystallography X-Ray Diffraction angiogenesis base cell growth regulation design extracellular in vitro testing in vivo inhibitor/antagonist mutant novel novel strategies physical model receptor vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Thrombospondin-1 (TSP1) and its receptors have long been thought to have important roles in regulating vascular cells, both circulating and mural. During the preceding grant period we have discovered that TSP1 and CD47 (integrin-associated protein) regulate the dynamic range of nitric oxide (NO) signaling in vascular cells. Thus TSP1-CD47 interactions are important not only in angiogenic regulation but in rapid regulation of tissue perfusion and many other roles where NO maintains the health of the cardiovascular system. We have identified the binding surface on the C-terminal domain of TSP1 that interacts with CD47. We have also discovered a new extracellular mechanism for integrin activation via CD47. This proposal focuses on the molecular interactions among TSP1, CD47 and 23 integrins. The molecular details of these interactions will be deduced by mutagenesis of all three interacting partners. Mutant proteins will be tested in vitro in binding assays and assays of CD47 and integrin function. The extracellular clasp mechanism for integrin activation that we identified within the 1v23 structure will be tested in cultured cells and in 23-null mice repopulated with bone marrow expressing activated 23 integrin constructs. A similar approach will test the ability of CD47 to activate 23 integrins via interaction with the clasp in cultured cells and in mice expressing mutant CD47 transgenes. Conditions for formation of TSP1-CD47 and CD47-integrin complexes will be evaluated using physical methods and several EM approaches. These methods will then be used to evaluate the interactions of mutant proteins in order to identify structural elements of each that are important for their molecular interactions. Based on these results, crystallization and X-ray diffraction studies will be initiated of CD47 in complexes with the TSP1 C-terminal domain and with 1v23 integrin. The sum of these studies will provide for the first time a physical model of TSP1-CD47-integrin interactions. Given our new paradigm for TSP1-CD47 regulation of NO signaling in the vascular system, this information will be vital in designing new strategies to modulate endogenous NO signaling, a new approach to ameliorating cardiovascular disease.

描述(申请人提供)：血栓反应蛋白-1(TSP1)及其受体长期以来一直被认为在调节循环和壁上的血管细胞方面具有重要作用。在前面的授权期，我们发现TSP1和CD47(整合素相关蛋白)调节血管细胞中一氧化氮(NO)信号的动态范围。因此，TSP1-CD47的相互作用不仅在血管生成调节中，而且在组织灌流的快速调节以及在NO维持心血管系统健康的许多其他作用中都是重要的。我们已经确定了TSP1的C-末端结构域上与CD47相互作用的结合面。我们还发现了一种通过CD47激活整合素的新的细胞外机制。本研究的重点是TSP1、CD47和23整合素之间的分子相互作用。这些相互作用的分子细节将通过所有三个相互作用伙伴的突变来推断。突变蛋白将在体外进行结合试验和CD47和整合素功能的试验。我们在1v23结构中确定的整合素激活的细胞外扣机制将在培养细胞和重新填充表达激活的23整合素结构的骨髓的23缺失小鼠中进行测试。类似的方法将在培养细胞和表达突变CD47转基因的小鼠中测试CD47通过与CLAP相互作用激活23整合素的能力。TSP1-CD47和CD47-整合素复合体的形成条件将使用物理方法和几种EM方法进行评估。然后这些方法将被用来评估突变蛋白质的相互作用，以确定每种蛋白质的结构元素对它们的分子相互作用是重要的。在这些结果的基础上，将开始CD47在与TSP1 C-末端结构域和与1v23整合素的复合物中的结晶和X射线衍射研究。这些研究的总和将首次提供TSP1-CD47-整合素相互作用的物理模型。鉴于我们对血管系统中NO信号的TSP1-CD47调节的新范式，这些信息对于设计新的策略来调节内源性NO信号将是至关重要的，这是一种改善心血管疾病的新方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A naturally occurring extracellular alpha-beta clasp contributes to stabilization of beta3 integrins in a bent, resting conformation.

DOI：
10.1021/bi8015108
发表时间：
2008-10
期刊：
Biochemistry
影响因子：
2.9
作者：
Anthony N. Vomund;S. Stuhlsatz-Krouper;J. Dimitry;Yuhua Song;W. Frazier
通讯作者：
Anthony N. Vomund;S. Stuhlsatz-Krouper;J. Dimitry;Yuhua Song;W. Frazier

Age-dependent regulation of skeletal muscle mitochondria by the thrombospondin-1 receptor CD47.

DOI：
10.1016/j.matbio.2010.12.004
发表时间：
2011-03
期刊：
MATRIX BIOLOGY
影响因子：
6.9
作者：
Frazier, Elfaridah P.;Isenberg, Jeff S.;Shiva, Sruti;Zhao, Lei;Schlesinger, Paul;Dimitry, Julie;Abu-Asab, Mones S.;Tsokos, Maria;Roberts, David D.;Frazier, William A.
通讯作者：
Frazier, William A.

Distortion of the catalytic domain of tissue-type plasminogen activator by plasminogen activator inhibitor-1 coincides with the formation of stable serpin-proteinase complexes.

纤溶酶原激活剂抑制剂-1对组织型纤溶酶原激活剂催化结构域的扭曲与稳定的丝氨酸蛋白酶抑制剂-蛋白酶复合物的形成同时发生。