Investigating the role of the P2Y2 nucleotide receptor in inflammation

研究 P2Y2 核苷酸受体在炎症中的作用

• 批准号: 7840970
• 负责人: LAURIE ERB
• 金额: $ 10.08万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840970
• 关键词: Address; Adhesions; Adhesives; Affect; Agonist; Antisense Oligonucleotides; Arterial Injury; Arteries; Astrocytoma; Bacteria; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Bone Marrow; CCL2 gene; CD47 Antigen; Carotid Arteries; Cell Adhesion Molecules; Cells; Chemotactic Factors; Chemotaxis; Chloride Ion; Chlorides; Co-Immunoprecipitations; Cultured Cells; Disease; E-Selectin; Emigrations; Endothelial Cells; Environment; Epithelial Cells; Event; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Heterotrimeric GTP-Binding Proteins; Hyperplasia; Immune; Immunoblotting; Immunoprecipitation; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrin Binding; Integrins; Knockout Mice; Lead; Leukocytes; Ligands; Mediating; Modeling; Molecular Biology; Mus; Myosin Light Chain Kinase; Neurons; Nucleotides; Phagocytosis; Pharmacotherapy; Phenotype; Play; Process; Proteins; Pump; RGD (sequence); RNA Interference; Receptor Activation; Regulation; Reporting; Research; Role; Signal Transduction; Signaling Molecule; Silicones; Site; Stress; Stress Fibers; Surface; T-Lymphocyte; Therapeutic procedure; Tissues; Transactivation; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vitronectin; Wound Healing; angiogenesis; cadherin 5; cell injury; cell motility; cofilin; extracellular; granulocyte; in vivo Model; injured; knock-down; macrophage; mast cell; migration; monocyte; mutant; neutrophil; nucleotide receptor; osteopontin; protein complex; protein expression; receptor; receptor expression; receptor function; receptor-mediated signaling; research study; therapy design

DESCRIPTION (provided by applicant): An essential feature of inflammation is the emigration of leukocytes from the blood into damaged or infected tissue. Several evidences suggest that extracellular nucleotides play a critical role in leukocyte emigration via activation of the P2Y2 subtype of nucleotide receptors (P2Y2R). Damaged cells as well as activated platelets, mast cells, macrophages, and nerve cells can release nucleotides into the extracellular environment where they activate many subtypes of nucleotide receptors. Activation of the P2Y2R subtype in monocytes, neutrophils, and other leukocytes has been shown to have a mitogenic and chemotactic effect on these cells. Furthermore, tissue damage or stress has been found to dramatically increase the expression of the P2Y2R in vascular endothelial cells and extravascular application of the P2Y2R agonist UTP to injured tissue enhances monocyte adhesion to endothelial cells and transendothelial migration of monocytes to the site of injury. We have found that the P2Y2R contains an integrin-binding domain that allows this receptor to associate with the aV¿3 integrin, an adhesion molecule that is important for both leukocyte migration and angiogenesis. Furthermore, integrin association with the P2Y2R has been found crucial for chemotaxis or cell migration towards extracellular nucleotides. The central hypothesis of this study is that leukocyte emigration caused by extracellular nucleotides is mediated by P2Y2Rs in both leukocytes and endothelial cells and is coordinately regulated by the association between P2Y2R and aV¿3 integrins. Our overall objective is to understand how tissue damage causes the body to mount an inflammatory response. Briefly, the studies in this proposal will 1) identify signaling molecules and protein complexes that are responsible for P2Y2R-mediated chemotaxis and 2) use the P2Y2R knockout mouse and an in vivo model of vascular injury to conclusively determine whether the P2Y2R is involved in recruitment of monocytes and other immune cells into damaged tissue. We suggest that a greater understanding of the mechanisms of P2Y2R function and regulation will lead to drug therapies that control inflammation. Nucleotides released from damaged tissue have been implicated as inducers of inflammation via activation of P2Y2 nucleotide receptors (P2Y2R) present on the surface of leukocytes and vascular endothelial cells. Therefore, the P2Y2R represents an exciting new target for controlling inflammation and our proposed research into the molecular biology of the P2Y2R should enable us to devise therapeutic procedures to stimulate or limit inflammatory responses mediated by this receptor.

描述（由适用提供）：炎症的基本特征是白细胞从血液中移民到损伤或感染组织。几个证据表明，细胞外核核苷酸通过激活核核苷酸受体（P2Y2R）的P2Y2亚型而在白细胞移民中起关键作用。受损的细胞以及活化的血小板，肥大细胞，巨噬细胞和神经细胞可以将核核苷酸释放到细胞外环境中，在那里它们激活许多核卫星受体的亚型。单核细胞，中性粒细胞和其他白细胞中P2Y2R亚型的激活已证明对这些细胞具有有丝分裂和趋化的作用。此外，已经发现组织损伤或应激大大增加了P2Y2R在血管内皮细胞中的表达，以及P2Y2R激动剂UTP在损伤组织中的血管外应用可增强单核细胞的粘合剂对内皮细胞的粘合剂，并在损伤部位的跨内皮细胞迁移。我们发现P2Y2R包含一个整联蛋白结合结构域，该结构域使该受体与Av？3整合蛋白相关，这是一种粘附分子，对于白细胞迁移和血管生成都很重要。此外，已发现整联蛋白与P2Y2R的关联对于趋化性或细胞向细胞外核动肽的迁移至关重要。这项研究的核心假设是，由细胞外核动脉动物引起的白细胞移民是由白细胞和内皮细胞中的P2Y2R介导的，并且由P2Y2R和AV¿3整联蛋白之间的关联协调调节。我们的总体目标是了解组织损伤如何导致人体安装炎症反应。简而言之，该提案中的研究将1）确定负责P2Y2R介导的趋化性的信号分子和蛋白质复合物，以及2）使用P2Y2R敲除小鼠和血管损伤的体内模型，以最终确定P2Y2R是否参与了Monocytes和其他Immiguno and Immanimuno Cells和其他损坏的组织中的招募。我们建议对P2Y2R功能和调节的机制有更深入的了解，将导致控制注射的药物疗法。通过受损组织释放的核苷酸已通过激活白细胞和血管内皮细胞表面上的P2Y2核肽受体（P2Y2R）而实现为炎症的影响者。因此，P2Y2R代表了控制感染的一个令人兴奋的新目标，我们对P2Y2R分子生物学的拟议研究应使我们能够设计治疗程序，以刺激或限制该接收器介导的炎症反应。