Role of chemokine receptors in neuronal survival

描述（由申请人提供）：本提案旨在确定阿片类药物是否控制趋化因子对中枢神经元的作用，并确定所涉及的细胞和分子机制。阿片类药物，趋化因子及其受体之间的功能和物理相互作用将进行研究，重点是μ-阿片激动剂对趋化因子CXCL 12（SDF-1），天然CXCR 4配体的神经元反应的调节作用。所提出的实验将检验阿片类调节CXCL 12的神经元作用（主要是参与神经元存活的细胞内途径的激活）的假设，并且这可能有助于CXCR 4在病理条件下的有害作用，例如neuroAIDS。第一个具体目标将提供阿片类药物干扰CXCR 4在培养的神经元中招募神经元存活途径的机制的见解。这些实验的目的是确定阿片类药物作用的主要靶点是CXCR 4还是其下游信号通路。第二个具体目标中提出的研究将集中在阿片类药物对CXCR 4作用的动力学上，并确定是否需要持续暴露于μ激动剂以抑制CXCL 12诱导的反应;这些实验还将研究体外和体内吗啡治疗的效果。这些信息将更好地表征阿片类药物对CXCL 12的作用，并帮助我们评估这种调节的潜在病理学意义，这将在第三个目标中进一步利用。这最后一个具体目标将评估μ阿片受体激动剂在HIV神经病理学背景下的作用，并关注μ阿片受体激活对HIV神经毒性的影响。将采用成熟的细胞和分子药理学的体外和离体技术，沿着更新颖的分子生物学和成像方法。拟议研究的长期目标是表征调节趋化因子对神经元作用的细胞和环境因素，这将导致更好地理解趋化因子在CNS中的生理和病理作用。此外，由于在有药物滥用史的患者中进展为神经艾滋病似乎更引人注目，这些研究也可能揭示阿片类药物和趋化因子之间未知的相关性，这可能对艾滋病毒感染的药物滥用者的临床管理和治疗有用。

DESCRIPTION (provided by applicant): This proposal aims to establish whether opioids control the effect of chemokines on central neurons and to identify the cellular and molecular mechanisms involved. Functional and physical interactions between opioids, chemokines and their receptors will be investigated, focusing on the modulatory action of mu-opioid agonists on neuronal responses to the chemokine CXCL12 (SDF-1), the natural CXCR4 ligand. The proposed experiments will test the hypothesis that opioids regulate the neuronal actions of CXCL12 (mainly the activation of intracellular pathways involved in neuronal survival) and that this may contribute to the deleterious effects of CXCR4 under pathological conditions, such as neuroAIDS. The first Specific Aim will provide insights into the mechanisms whereby opioids interfere with recruitment of neuronal survival pathways by CXCR4 in cultured neurons. The goal of these experiments is to establish whether the primary target of opioid action is CXCR4 or its downstream signaling pathways. The studies proposed in the second Specific Aim will focus on the kinetics of the opioids action on CXCR4 and determine whether continued exposure to mu-agonists is required to inhibit CXCL12-induced responses; also these experiments will study the effects of in vitro and in vivo morphine treatments. This information will better characterize the action of opioids on CXCL12 and help us evaluate the potential pathological implications of such regulation, which will be further exploited in the third aim. This last Specific Aim will evaluate the role of mu-opioid agonists in the context of HIV neuropathology and focus on the effect of mu-opioid receptor activation on HIV neurotoxicity. Well-established in vitro and ex vivo techniques of cellular and molecular pharmacology will be employed, along with more novel molecular biology and imaging approaches. The long-term goal of the proposed studies is to characterize the cellular and environmental factors that regulate the action of chemokines on neurons, which will lead to a better understanding of the physiological and pathological role of chemokines in the CNS. Furthermore, as progression to neuroAIDS appears more dramatic in patients with history of drug abuse, these studies may also reveal unknown correlations between opioids and chemokines that might be useful to the clinical management and therapy of HIV-infected drug abusers.