Role of beta-arrestin-dependent chemotaxis in protease-activated-receptor-2-induc

β-抑制蛋白依赖性趋化作用在蛋白酶激活受体 2 诱导中的作用

• 批准号: 7596895
• 负责人: Kathryn Anne DeFea
• 金额: $ 14.63万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596895
• 关键词: Address; Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Arrestins; Asthma; Blood; Bone Marrow; Bone Marrow Transplantation; Boxing; Cells; Chemotaxis; Colitis; Couples; Coupling; Development; Dinoprostone; Disease; Disease model; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelium; Evaluation; Event; Extrinsic asthma; Figs - dietary; G-Protein-Coupled Receptors; GTP-Binding Proteins; Grant; Immune; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Intranasal Administration; Invaded; Knockout Mice; LIMK1 gene; Laboratories; Lead; Leukocytes; Life; Lung; Lung Lavage Fluid; Malignant Neoplasms; Measures; Mediating; Microscopy; Migration Assay; Modeling; Monitor; Mucous Membrane; Mus; Muscle relaxation phase; Nuclear; PAR-2 Receptor; PTGS2 gene; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Physiological; Principal Investigator; Production; Prostaglandin Production; Protein Family; Proteins; Reading; Recruitment Activity; Relaxation; Role; Sepharose; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Smooth Muscle; Smooth Muscle Myocytes; Testing; Theft; Therapeutic; Transplantation; Trypsin; Western Blotting; aerosolized; arrestin 1; arrestin 2; beta-arrestin; cell type; cofilin; cytokine; in vivo; inflammatory marker; inhibitor/antagonist; interest; novel; pathogen; programs; protective effect; public health relevance; receptor; receptor coupling; response; therapeutic target

DESCRIPTION (provided by applicant): Protease-activated-receptor-2 (PAR-2) is a G-protein-coupled-receptor (GPCR) activated by a number of trypsin-like proteases, many of which are found at sites of inflammation or may be released by invading pathogens(5; 7). Current studies indicate that PAR-2 may have both protective and pathogenic effects in inflammatory diseases such as asthma and colitis, depending on the disease model, the administration of PAR-2 agonist and the physiological read-out (1-4; 8; 11; 14-16). Our laboratory has demonstrated multiple G-protein-independent effects of PAR-2, that are mediated by a family of proteins called 2-arrestins (6; 9; 10; 13; 17; 18). 2-arrestins effectively 'steal' signaling molecules from the G-protein pathway, some of which they directly inhibit others of which are activated only in specific cellular microdomains. Additionally, 2-arrestins can recruit and activate molecules not affected by G-protein coupling (17; 18). This 2-arrestin-dependent PAR2 signaling mechanism allows one receptor to orchestrate different physiological events in a cell-type specific manner. Recently, there has been a substantial amount of interest in PAR-2 as a therapeutic target for asthma and other inflammatory disorders (4; 12); however, while some groups propose agonists others propose antagonists of PAR2 as therapeutics. This grant tests the novel hypothesis that 2-arrestin-dependent and G-protein-dependent signals may dominate in different cell types leading to some inflammatory and some protective responses, by assessing PAR2 evoked asthma in mice lacking either of the two 2-arrestins (knockout mice), and by transplanting bone marrow of PAR-2 knockout mice into wild type. Elucidation of the specific role of each signaling pathway in inflammation could lead to the development of pathway specific PAR2 agonists and/or antagonists. Public Health Relevance: Currently Protease-activated-receptor-2 (PAR2) is being considered as a target for treatment of asthma, colitis and cancer; however, there exists considerable controversy over its actual role in inflammation. Some groups are proposing aerosolized activators as a treatment for asthma, while others propose antagonizing it to achieve suppression of inflammation. This proposal aims to dissect the pathways leading to pro and anti-inflammatory effects of PAR-2 in the airways, with the hope that this may lead to the eventual development of pathway-specific drugs.

描述（由申请人提供）：蛋白酶激活受体2（PAR-2）是一种G蛋白偶联受体（GPCR），由多种胰蛋白酶样蛋白酶激活，其中许多蛋白酶样蛋白酶存在于炎症部位或可能由入侵病原体释放（5; 7）。目前的研究表明，PAR-2可能在炎症性疾病如哮喘和结肠炎中具有保护作用和致病作用，这取决于疾病模型、PAR-2激动剂的施用和生理读数（1-4; 8; 11; 1 - 4 -16）。我们的实验室已经证明了PAR-2的多种G蛋白非依赖性作用，这些作用由称为2-arrestins的蛋白质家族介导（6; 9; 10; 13; 17; 18）。2-抑制蛋白有效地从G蛋白途径“窃取”信号分子，其中一些直接抑制，另一些仅在特定的细胞微区被激活。此外，2-arrestins可以募集和激活不受G蛋白偶联影响的分子（17; 18）。这种2-arrestin依赖性PAR 2信号传导机制允许一种受体以细胞类型特异性方式协调不同的生理事件。最近，PAR-2作为哮喘和其他炎性疾病的治疗靶点引起了很大的兴趣（4; 12）;然而，尽管一些研究组提出了PAR-2的激动剂，但另一些研究组提出了PAR-2的拮抗剂作为治疗剂。这项研究通过评估缺乏两种2-arrestins的小鼠（敲除小鼠）中PAR 2诱发的哮喘，并通过将PAR-2敲除小鼠的骨髓移植到野生型小鼠中，验证了新的假设，即2-arrestin依赖性和G蛋白依赖性信号可能在不同的细胞类型中占主导地位，导致一些炎症和一些保护性反应。阐明每种信号传导途径在炎症中的特定作用可能导致途径特异性PAR 2激动剂和/或拮抗剂的开发。 公共卫生相关性：目前，蛋白酶激活受体2（PAR 2）被认为是治疗哮喘、结肠炎和癌症的靶点;然而，关于其在炎症中的实际作用存在相当大的争议。一些团体提出雾化活化剂作为哮喘的治疗方法，而另一些团体则提出拮抗它以抑制炎症。该提案旨在剖析导致气道中PAR-2的促炎和抗炎作用的途径，希望这可能导致最终开发途径特异性药物。