Molecular and Functional Characterization of Chemerin Receptors

Chemerin 受体的分子和功能表征

基本信息

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
项目类别：
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

项目摘要

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）：该项目的总体目标是确定凯莫瑞受体 CMKLR1 和 CCRL2 在白细胞运输、功能和实验性自身免疫性脑脊髓炎 (EAE)（多发性硬化症小鼠模型）的病理生理学中的作用。初步结果表明，CMKLR1 是一种整合素触发趋化受体，由巨噬细胞、NK 细胞表达，并由活化的树突状细胞上调； CCRL2 是一种非信号凯莫瑞“递送”受体，由肥大细胞、活化的巨噬细胞和内皮细胞表达，可结合凯莫瑞并调节引诱剂的生物利用度；凯莫瑞受体在调节体内炎症反应中发挥着关键作用。目标 1 下的研究将确定凯莫瑞是否可以诱导 CMKLR1 介导的整合素触发以及巨噬细胞和 NK 细胞的快速粘附。这些研究对于了解 CMKLR1 如何促进体内巨噬细胞和 NK 转运（其中凯莫林被炎症或凝血相关蛋白酶激活）具有重要意义。目标 2 下的研究测试了以下假设：CCRL2 是一种非信号传导凯莫瑞“递送”受体，用于集中和呈递活性化学引诱剂。这些研究将阐明 CCRL2 在调节凯莫瑞活性及其通过 CMKLR1 体内信号传导方面的功能意义。目标 3 将定义 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抗 mCMKLR1 阻断单克隆抗体将用于研究这些受体对动物疾病进展的影响。将检查局部白细胞浸润、功能和细胞因子产生，以确定受体促进或调节体内炎症和免疫反应的机制。总之，这些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。它们可能会产生预防或治疗自身免疫性疾病的新靶点或方法。公共健康相关性：该研究项目有可能确定预防和/或治疗多发性硬化症等自身免疫性疾病的新靶标。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来治疗改变组织损伤和炎症部位关键白细胞群的积累和/或功能。