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因子受体CMKLR 1和CCRL 2在白细胞运输、功能和实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症的小鼠模型）的病理生理学中的作用。初步结果表明，CMKLR1是一种由巨噬细胞、NK细胞表达并由活化的树突状细胞上调的整合素触发化学引诱物受体; CCRL 2是一种由肥大细胞、活化的巨噬细胞和内皮细胞表达的非信号趋化素"递送"受体，其结合趋化素并用于调节引诱物的生物利用度;并且chemerin受体在体内调节炎症反应中起关键作用。目标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介导的整合素触发和快速粘附。这些研究将对理解CMKLR1如何促进体内巨噬细胞和NK运输具有重要意义，其中chemerin被炎症或凝血相关蛋白酶激活。目标2下的研究测试了CCRL2是用于浓缩和呈递活性化学引诱物的非信号传导趋化素"递送"受体的假设。这些研究将阐明CCRL 2在体内调控chemerin活性及其通过CMKLR 1信号传导的功能意义。目的3明确CMKLR 1和CCRL 2在实验性自身免疫性脑脊髓炎（EAE）病理生理中的作用。CMKLR1或CCRL 2遗传缺陷小鼠以及抗mCMKLR1阻断mAb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。它们可能会导致新的目标或方法，用于预防或治疗自身免疫性疾病。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（如多发性硬化症）的新靶点。该项目将提高我们对白色血细胞运输的理解，并可能提供新的方法来治疗性地改变组织损伤和炎症部位关键白色血细胞群体的积累和/或功能。

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.