Molecular and Functional Characterization of Chemerin Receptors

描述（由申请人提供）：本项目的总体目标是确定趋化素受体CMKLR1和CCRL2在实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症小鼠模型）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是一种整合素触发的化学引诱受体，由巨噬细胞、NK细胞表达，并被活化的树突状细胞上调；CCRL2是一种非信号化趋化素“传递”受体，由肥大细胞、活化的巨噬细胞和内皮细胞表达，可结合趋化素并调节引诱剂的生物利用度；趋化素受体在调节体内炎症反应中起着关键作用。Aim 1下的研究将确定趋化素是否可以诱导cmklr1介导的整合素触发和巨噬细胞和NK细胞的快速粘附。这些研究将对了解CMKLR1如何促进体内巨噬细胞和NK运输具有重要意义，其中趋化素被炎症或凝固相关蛋白酶激活。Aim 2下的研究验证了CCRL2是一种非信号化趋化素“传递”受体的假设，其作用是集中和呈递活性趋化剂。这些研究将阐明CCRL2在体内通过CMKLR1调节趋化素活性及其信号传导中的功能意义。目的3将确定CMKLR1和CCRL2在实验性自身免疫性脑脊髓炎（EAE）病理生理中的作用。CMKLR1或CCRL2基因缺陷的小鼠，以及抗mcmklr1阻断单抗，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、功能和细胞因子的产生，以确定受体在体内参与或调节炎症和免疫反应的机制。总之，这些研究有望确定巨噬细胞、肥大细胞和NK细胞生物学和功能的关键调控机制。它们可能导致预防或治疗自身免疫性疾病的新靶点或新方法。公共卫生相关性：该研究项目有潜力确定预防和/或治疗自身免疫性疾病（如多发性硬化症）的新靶点。该项目将提高我们对白细胞运输的理解，并可能为治疗改变组织损伤和炎症部位关键白细胞群的积累和/或功能提供新方法。

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.