Inflammation in Vascular Injury and Repair

血管损伤与修复中的炎症

• 批准号: 8184147
• 负责人: Daniel I Simon
• 金额: $ 47.28万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8184147
• 关键词: Adhesives; Affect; Affinity; Alanine; Ally; Animals; Arthritis; Atherosclerosis; Award; Binding; Binding Sites; Biochemical; Biological Assay; Bleeding time procedure; Blocking Antibodies; Blood; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular Diseases; Carotid Arteries; Cell Lineage; Cells; Clinical Research; Colony-Stimulating Factor Receptors; Common carotid artery; Complex; Data; Defect; Development; Disease; Dose; Drug Design; Fibrinogen; Functional disorder; Gene Expression; Generations; Genes; Glean; Glomerulonephritis; Grant; Hemostatic function; Human; ITGAM gene; ITGB2 gene; Immunoglobulin G; Inflammation; Inflammatory; Inflammatory Response; Injury; Instruction; Integrins; Intercellular adhesion molecule 1; Knock-in Mouse; Laboratories; Laser injury; Lasers; Lead; Length; Leukocytes; Ligands; Light; Macrophage-1 Antigen; Manuscripts; Mediating; Methyl Green; Modeling; Molecular; Molecular Conformation; Monitor; Monoclonal Antibodies; Mouse Strains; Multiple Sclerosis; Mus; Mutation; N-terminal; Nature; P-Selectin; P-selectin ligand protein; Pathogenesis; Pathway interactions; Peptides; Phagocytosis; Phenotype; Phosphate Buffer; Phosphorylation; Physiological; Physiology; Platelet Activation; Play; Positioning Attribute; Principal Investigator; Process; Production; Progress Reports; Property; Publishing; Reagent; Recruitment Activity; Regulation; Reporting; Repression; Respiratory Burst; Rest; Right common carotid artery structure; Role; Rose Bengal; Rupture; Saline; Series; Signal Transduction; Site; Source; Specificity; Surface Plasmon Resonance; System; Tail; Targeted Research; Testing; Therapeutic; Thromboplastin; Thrombosis; Thrombus; Time; Tissues; Transcription Repressor/Corepressor; Transgenic Mice; Vasculitis; Veins; Work; anti-IgG; artery occlusion; atherothrombosis; base; c-fms Proto-Oncogenes; cell type; cytokine; forkhead protein; in vivo; inhibitor/antagonist; injury and repair; innovation; insight; mRNA Differential Displays; macrophage; monocyte; neutrophil; novel; novel therapeutic intervention; overexpression; programs; promoter; receptor; research study; response; small molecule; tool; transcription factor

For the past 14 years, our laboratory has been at the forefront of studies investigating the role of inflammation in vascular injury and repair. Adhesive interactions between vascular cells orchestrate this inflammatory response. During the period of this grant (years 11-14), we have continued to focus on the leukocyte integrin Mac-1 (aMPa. CD11b/CD18), identifying this adhesive receptor as a critical molecular determinant of leukocyte recruitment and signaling. Our laboratory first reported the interaction between Mac-1 and its platelet counter-receptor GP Iba and determined the molecular basis of GP Iba recognition, identifying the P201-K217 sequence within the aMi-domain as the binding site for GP Iba, We established that leukocyte engagement of platelet GP Iba via Mac-1 is critical for vascular injury and repair, and have made important new discoveries that the Mac-1-GP Iba interaction broadly regulates inflammation in models of thrombosis, vasculitis, glomerulonephritis, and multiple sclerosis. Further, the signaling capacity of Mac-1 was explored and using a differential display strategy we cloned a novel forkhead transcription factor, Foxpl, which is regulated by Mac-1 signaling and controls monocyte differentiation. Together these observations reveal novel information as to how leukocytes are recruited at sites of vascular injury and how integrins are regulated and initiate "outside-in" signals, suggesting new opportunities for manipulation of integrin function in vivo. These findings are the basis for this MERIT extension application. The central hypothesis of this proposal Is that the interaction of leukocyte Mac-1 with platelet GP Iba is broadly required for inflammation and initiates pro-inflammatory and pro-thrombotic signals that promote diverse disease processes. The overall objective of this proposal is to define the role of the Mac-1-GP Iba interaction in inflammation and thrombosis. Our specific aims are: (1) To define the physical determinants of the interactions between Mac-1-GP Iba and the nature of "outside-in" signals generated by this interaction; (2) To develop a small molecule inhibitor of Mac-1-GP Iba; (3) To investigate the role of Mac-1-GP Iba in the dynamic process of thrombosis; and (4) To determine the effect of disrupting Mac-1-GP Iba on diverse disease processes, including models of atherosclerosis, arthritis, and multiple sclerosis. Because leukocyte- platelet interactions broadly regulate inflammation, understanding the molecular machinery of this cellular complex will provide important insights for developing new therapies directed at inflammatory diseases, including atherosclerosis, thrombosis, vasculitis, arthritis, and multiple sclerosis. RELEVANCE (See instructions): We discovered that the interaction between leukocyte integrin Mac-1 and platelet GP Iba is critical for vascular injury and repair and now provide evidence that the Mac-1-GP Iba interaction broadly regulates inflammation in diverse disease processes. The results of these studies will provide important insights for developing new therapies directed at inflammatory diseases, including atherosclerosis, thrombosis, vasculitis, arthritis, and multiple sclerosis.

在过去的14年里，我们的实验室一直处于研究的最前沿， 炎症在血管损伤和修复中作用。血管细胞之间的粘附相互作用协调了这一过程 炎症反应。在此资助期间（11-14年级），我们继续专注于 白细胞整合素Mac-1（aMPa. CD 11b/CD 18），将这种粘附受体确定为关键分子 白细胞募集和信号传导的决定因素。我们的实验室首次报道了 Mac-1与血小板反受体GP Iba的相互作用，确定了GP Iba识别的分子基础， 通过鉴定α Mi结构域中的P201-K217序列作为GP Iba的结合位点，我们建立了 白细胞通过Mac-1参与血小板GP Iba对于血管损伤和修复至关重要， 有重要的新发现，Mac-1-GP Iba相互作用广泛调节模型中的炎症 血栓、血管炎、肾小球肾炎和多发性硬化症。此外，Mac-1的信令容量 我们利用差异显示技术克隆了一个新的叉头转录因子Foxpl， 其受Mac-1信号传导调节并控制单核细胞分化。这些观察结果 揭示了新的信息，白细胞是如何在血管损伤部位招募和整合素是如何被激活的。 调节和启动“由外向内”的信号，提示新的机会，操纵整合素的功能 in vivo.这些调查结果是MERIT延期申请的基础。这个问题的核心假设是 建议是白细胞Mac-1与血小板GP Iba的相互作用是广泛需要的， 炎症并启动促炎和促血栓形成信号， 疾病过程。本提案的总体目标是确定Mac-1-GP Iba的作用 炎症和血栓形成的相互作用。我们的具体目标是：（1）定义的物理决定因素， Mac-1-GP Iba之间的相互作用以及这种相互作用产生的“由外而内”信号的性质; (2)（3）研究Mac-1-GP Iba在肿瘤细胞凋亡中的作用。 研究干扰Mac-1-GP Iba对血栓形成的动态过程的影响。 疾病过程，包括动脉粥样硬化、关节炎和多发性硬化的模型。因为白细胞- 血小板相互作用广泛地调节炎症，了解这种细胞的分子机制， 复合物将为开发针对炎症性疾病的新疗法提供重要的见解， 包括动脉粥样硬化、血栓形成、血管炎、关节炎和多发性硬化。 相关性（参见说明）： 我们发现，白细胞整合素Mac-1和血小板GP Iba之间的相互作用是至关重要的， 血管损伤和修复，现在提供的证据表明，Mac-1-GP Iba相互作用广泛调节 炎症在不同的疾病过程中。这些研究的结果将提供重要的见解， 开发针对炎性疾病的新疗法，包括动脉粥样硬化，血栓形成， 血管炎关节炎和多发性硬化症