Molecular and Functional Characterization of Chemerin Receptors

Chemerin 受体的分子和功能表征

• 批准号: 8102145
• 负责人: BRIAN A. ZABEL
• 金额: $ 31.58万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102145
• 关键词: Adhesions; Animals; Autoimmune Diseases; Binding; Biological Availability; Cell physiology; Cells; Cellular biology; Chemotactic Factors; Coagulation Process; Dendritic Cells; Disease Progression; Dissociation; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; Functional disorder; Goals; Health; Immune response; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integrins; Kinetics; Lead; Leukocyte Trafficking; Leukocytes; Mediating; Methods; Molecular; Multiple Sclerosis; Mus; Natural Killer Cells; Peptide Hydrolases; Play; Population; Prevention; Prevention approach; Production; Receptor Signaling; Regulation; Research Project Grants; Role; Signal Transduction; Site; Stimulus; Testing; Tissues; beta-Chemokines; cell type; cytokine; fMet-Leu-Phe receptor; human CCL15 protein; human CMKLR1 protein; improved; in vivo; macrophage; mast cell; mouse model; novel; receptor; receptor binding; receptor function; research study; trafficking

DESCRIPTION (provided by applicant): The overall objective of this project is to define the role of chemerin receptors CMKLR1 and CCRL2 in leukocyte trafficking, function, and the pathophysiology of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Preliminary results suggest that CMKLR1 is an integrin-triggering chemoattractant receptor expressed by macrophages, NK cells, and upregulated by activated dendritic cells; CCRL2 is a non-signaling chemerin "delivery" receptor expressed by mast cells, activated macrophages and endothelial cells that binds chemerin and serves to regulate the bioavailability of the attractant; and that the chemerin receptors play critical roles in modulating inflammatory responses in vivo. Studies under Aim 1 will determine if chemerin can induce CMKLR1-mediated integrin triggering and rapid adhesion in macrophages and NK cells. These studies will have important implications for understanding how CMKLR1 contributes to macrophages and NK trafficking in vivo where chemerin is activated by inflammation or coagulation-associated proteases. Studies under Aim 2 test the hypothesis that CCRL2 is a non-signaling chemerin "delivery" receptor that serves to concentrate and present active chemoattractant. These studies will elucidate the functional significance of CCRL2 in regulating chemerin activity and its signaling via CMKLR1 in vivo. Aim 3 will define the roles of CMKLR1 and CCRL2 in the pathophysiology of experimental autoimmune encephalomyelitis (EAE). Mice genetically deficient in CMKLR1 or CCRL2, as well as anti-mCMKLR1 blocking mAbs, will be used to investigate the contribution of these receptors to disease progression in animals. Local leukocyte infiltration, function, and cytokine production will be examined to define the mechanisms by which the receptors contribute to or modulate inflammation and immune responses in vivo. Together, the studies proposed promise to define a key regulatory mechanism in macrophage, mast cell, and NK cell biology and function. They may lead to novel targets or approaches for the prevention or treatment of autoimmune disease. PUBLIC HEALTH RELEVANCE: This research project has the potential to identify novel targets for the prevention and/or treatment of autoimmune diseases, such multiple sclerosis. This project will improve our understanding of white blood cell trafficking, and may offer new methods for therapeutically altering the accumulation and/or function of critical white blood cell populations at sites of tissue damage and inflammation.

描述（由申请人提供）：该项目的总体目的是定义化学蛋白受体CMKLR1和CCRL2在白细胞运输，功能以及实验性自身免疫性脑脊髓炎（EAE）的病理生理学中的作用，一种多发性硬化症的小鼠模型。初步结果表明，CMKLR1是一种整联蛋白触发的化学吸引剂受体，该受体由巨噬细胞，NK细胞表达，并由活化的树突状细胞上调。 CCRL2是由肥大细胞表达的非信号化学“递送”受体，激活的巨噬细胞和内皮细胞结合了化学蛋白，并用于调节吸引剂的生物利用度；并且化学受体在调节体内炎症反应中起关键作用。 AIM 1下的研究将确定Chemerin是否可以诱导巨噬细胞和NK细胞中CMKLR1介导的整联蛋白触发和快速粘附。这些研究将对理解CMKLR1如何促进巨噬细胞和NK运输在体内具有重要意义，在该体内，Chemerin被炎症或与凝结相关的蛋白酶激活。 AIM 2的研究检验了CCRL2是一种非信号化学蛋白的“递送”受体的假设，可用于浓缩并呈现活跃的趋化剂。这些研究将阐明CCRL2在调节化学活性及其通过体内CMKLR1信号传导中的功能意义。 AIM 3将定义CMKLR1和CCRL2在实验自身免疫性脑脊髓炎（EAE）的病理生理中的作用。在遗传上缺乏CMKLR1或CCRL2的小鼠以及抗MCMKLR1阻断mAb的小鼠将用于研究这些受体对动物疾病进展的贡献。将检查局部白细胞浸润，功能和细胞因子产生，以定义受体在体内促进或调节炎症和免疫反应的机制。共同提出的研究有望定义巨噬细胞，肥大细胞和NK细胞生物学和功能的关键调节机制。它们可能导致预防或治疗自身免疫性疾病的新目标或方法。公共卫生相关性：该研究项目有可能确定预防和/或治疗自身免疫性疾病（这种多发性硬化症）的新目标。该项目将提高我们对白细胞运输的理解，并可能提供新的方法，用于改变组织损伤和炎症部位的关键白细胞种群的积累和/或功能。