Molecular and Functional Characterization of Chemerin Receptors

Chemerin 受体的分子和功能表征

• 批准号: 7741831
• 负责人: BRIAN A. ZABEL
• 金额: $ 31.36万
• 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/7741831
• 关键词: Adhesions; Animals; Autoimmune Diseases; Binding; Biological Availability; CCRL2 gene; Cells; Cellular biology; Chemotactic Factors; Coagulation Process; Dendritic Cells; Disease Progression; Dissociation; Encephalomyelitis; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; Functional disorder; Goals; 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 CMKLR1 protein; improved; in vivo; macrophage; mast cell; mouse model; novel; public health relevance; 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(申请人提供)：本项目的总体目标是确定趋化蛋白受体CMKLR1和CCRL2在多发性硬化症小鼠模型实验性自身免疫性脑脊髓炎(EAE)的白细胞运输、功能和病理生理学中的作用。初步结果表明，CMKLR1是由巨噬细胞、NK细胞表达的整合素触发的趋化因子受体，由激活的树突状细胞上调；CCRL2是由肥大细胞、活化的巨噬细胞和内皮细胞表达的非信号趋化蛋白递送受体，与趋化蛋白结合并调节诱导剂的生物利用度；趋化蛋白受体在体内调节炎症反应中起关键作用。根据目标1的研究将确定趋化蛋白是否可以诱导CMKLR1介导的整合素触发和巨噬细胞和NK细胞的快速黏附。这些研究将对理解CMKLR1如何在体内巨噬细胞和NK运输中发挥作用，其中趋化蛋白被炎症或凝血相关酶激活具有重要意义。AIM 2下的研究验证了CCRL2是一种非信号趋化蛋白“递送”受体的假设，该受体用于浓缩和递送活性化学诱导剂。这些研究将阐明CCRL2在体内通过CMKLR1调节趋化蛋白活性及其信号转导的功能意义。目的3明确CMKLR1和CCRL2在实验性自身免疫性脑脊髓炎(EAE)病理生理学中的作用。CMKLR1或CCRL2基因缺陷的小鼠，以及mCMKLR1抗体阻断单抗，将被用来研究这些受体在动物疾病进展中的作用。将检查局部白细胞的渗透、功能和细胞因子的产生，以确定受体在体内促进或调节炎症和免疫反应的机制。总之，这些研究提出了定义巨噬细胞、肥大细胞和NK细胞生物学和功能的关键调控机制的前景。它们可能导致预防或治疗自身免疫性疾病的新靶点或方法。公共卫生相关性：这项研究项目有可能确定预防和/或治疗自身免疫性疾病的新靶点，如多发性硬化症。这个项目将提高我们对白细胞贩运的理解，并可能提供新的方法来从治疗上改变组织损伤和炎症部位的关键白细胞群体的聚集和/或功能。