Role of chemokine receptors in neuronal survival

描述（由申请人提供）：本提案源于之前资助期间进行的研究，该研究揭示了趋化因子CXCL12及其主要受体CXCR4在中枢神经元和胶质细胞中的新颖和意想不到的作用。具体来说，本提案的目的是表征CXCL12对树突棘的作用，树突棘在神经保护和突触可塑性中起关键作用，并研究阿片类药物和HIV蛋白对这种作用的调节。这些研究将描述CXCL12引起的树突棘改变的分子机制；确定阿片类药物和HIV蛋白对cxcl12诱导的变化的影响；并在HIV神经病理学和药物滥用的背景下确定这些改变的潜在行为后果。这将通过体外和体内方法以及细胞/分子神经生物学和行为的各种技术来完成。本研究的长期目标是确定辅助神经保护治疗的药理学靶点，可能用于减少HIV患者的神经问题，从而协助临床管理高危神经病理学人群，如静脉注射吸毒者。aim 1中提出的研究将提供CXCL12诱导树突脊柱变化的动力学和机制的详细信息，并确认CXCL12/CXCR4轴在体内脊柱调节中的作用（主要关注前额叶皮层和海马）。我们期望结果支持CXCL12调节控制突触数量的基因程序表达的假设，最终导致更多的脊柱。总的来说，这些实验旨在证实CXCL12/CXCR4在维持健康树突乔木中的作用，并为目标2和目标3中将要进行的一些分析提供信息。目的2中的实验对于确定吗啡和HIV病毒蛋白（或由这些蛋白诱导的细胞因子）是否影响CXCL12对树突棘的调节具有重要意义。与aim 3的结果一起，这些发现将表明吗啡和HIV是否可以通过抑制这种体内平衡趋化因子的正常功能而导致神经元损伤。最后，aim 3的研究将揭示WT和HIV- tg大鼠在行为表现（涉及前额叶皮层和海马）方面的微妙但重要的差异，这将有助于我们描述与大脑中HIV病毒蛋白表达相关的特定缺陷，以及吗啡/CXCR4拮抗剂引起的CXCR4功能损伤。

DESCRIPTION (provided by applicant): The present proposal stems from research conducted during previous funding periods that revealed novel and unexpected roles of the chemokine CXCL12, and its primary receptor CXCR4, on central neurons and glia. Specifically, the objectives of this proposal are to characterize the effect of CXCL12 on dendritic spines, which are critically involved in neuroprotection and synaptic plasticity, and to study the modulation of this effect by opiates and HIV proteins. The proposed studies will characterize the molecular mechanisms involved in the dendritic spine changes evoked by CXCL12; determine the effect of opiates and HIV proteins on CXCL12-induced changes; and establish the potential behavioral consequences of these alterations in the context of HIV neuropathology and drug abuse. This will be accomplished using both in vitro and in vivo approaches and various techniques of cellular/molecular neurobiology and behavior. The long-term goal of this research is to identify pharmacological targets for adjuvant neuroprotective treatments that may be used to reduce neurological problems in HIV patients, thus assisting in the clinical management of populations at high risk of neuropathology, such as intravenous drug users. The studies proposed in aim 1 will provide detailed information about the kinetics and mechanisms involved in CXCL12-induced dendritic spine changes and confirm the role of the CXCL12/CXCR4 axis in the regulation of spines in vivo (with a major focus on the prefrontal cortex and hippocampus). We expect the results to support the hypothesis that CXCL12 regulates expression of gene programs that control synapse number, which ultimately results in more spines. Overall, these experiments intend to confirm the role of CXCL12/CXCR4 in maintenance of a healthy dendritic arbor and to inform some of the analysis to be conducted in aim 2 and 3. The experiments in aim 2 are important to determine if morphine and HIV viral proteins (or cellular factors induced by these proteins) affect the CXCL12 regulation of dendritic spines. Along with the results from aim 3, these findings will indicate whether morphine and HIV can precipitate neuronal damage by inhibiting normal function of this homeostatic chemokine. Finally, studies in aim 3 will unveil subtle but important differences in behavioral performance (involving the prefrontal cortex and hippocampus) between WT and HIV-Tg rats that will help us characterize the specific deficits associated with expression of HIV viral proteins in the brain as well as impairment of CXCR4 function caused by morphine/CXCR4 antagonists.