Role of chemokine receptors in neuronal survival

描述(申请人提供)：这项建议旨在确定阿片类药物是否控制趋化因子对中枢神经元的影响，并确定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被研究，重点是u-阿片激动剂对趋化因子CXCL12(SDF-1)(天然的CXCR4配体)的神经元反应的调制作用。拟议的实验将检验这样一种假设，即阿片类药物调节CXCL12的神经元活动(主要是激活参与神经元生存的细胞内通路)，这可能有助于在病理条件下CXCR4的有害影响，如神经艾滋病。第一个具体目标将提供对阿片类药物干扰CXCR4在培养神经元中重新招募神经元生存通路的机制的深入了解。这些实验的目的是确定阿片类药物作用的主要靶点是否是CXCR4或其下游信号通路。第二个具体目标中提出的研究将集中在阿片类药物对CXCR4的作用动力学，并确定是否需要持续暴露于u激动剂以抑制CXCL12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。这些信息将更好地描述阿片类药物对CXCL12的作用，并帮助我们评估这种调控的潜在病理影响，这将在第三个目标中得到进一步利用。最后一个具体目标将评估u-阿片激动剂在艾滋病毒神经病理学背景下的作用，并侧重于u-阿片受体激活对艾滋病毒神经毒性的影响。将采用成熟的细胞和分子药理学的体外和体外技术，以及更新的分子生物学和成像方法。这项研究的长期目标是表征调控趋化因子对神经元作用的细胞和环境因素，这将有助于更好地理解趋化因子在中枢神经系统中的生理和病理作用。此外，由于有药物滥用史的患者进展为神经艾滋病的可能性更大，这些研究还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.