Role of chemokine receptors in neuronal survival

趋化因子与艾滋病和神经炎性疾病的神经发病机制有关。然而，由于神经细胞和非神经细胞都在中枢神经系统中表达趋化因子受体，目前尚不清楚细胞类型特异性受体在多大程度上介导趋化因子对神经元的影响。关于趋化因子在各种生理和病理条件下对神经元有益或有害的可能性也存在争议，它们的作用受到其他内源性系统（如阿片样物质）活性的影响。我们的研究旨在确定趋化因子对神经元的直接作用，而不依赖于它们对炎症细胞和神经胶质细胞的作用，并确定调节神经元趋化因子受体活性的分子机制，包括它们与主要神经递质和神经肽系统的相互作用。本应用程序将研究神经元趋化因子受体在大鼠和人类神经元纯种群存活中的作用。我们的初步数据提出的假设是，这些受体在支持神经元存活中起重要作用，它们的异常激活导致神经元死亡。为了验证这一假设，首先要解决的问题是个体趋化因子受体（即CXCR4）是否可能与神经营养和神经毒性途径结合。为此，还将研究神经元CXCR4与神经毒性HIV-1蛋白gp120的相互作用。因此，趋化因子和gp120在不同实验条件下诱导受体磷酸化、二聚化和脱敏的能力将被研究。在与趋化因子和gp120结合后，趋化因子受体的分子活化/失活的差异将被检查，以评估这是否可能导致不同效应物的募集，对神经元存活产生相反的结果。最后，我们将研究谷氨酸和阿片类药物对趋化因子受体功能和表达的调节，以测试这些系统同时激活所施加的另一种或额外水平的调节的可能性，从而改变趋化因子对神经元信号传导和存活的影响。将采用生化、分子生物学、药理学和影像学等方法研究趋化因子受体的激活，并测试其对神经元存活和凋亡的细胞内通路的影响。这些研究将帮助我们了解趋化因子在中枢神经系统中的生理作用，以及它们在HIV神经病理学、神经炎性疾病以及与药物滥用相关的神经病理学中的作用。

Chemokines have been implicated in the neuropathogenesis of AIDS and neuro-inflammatory disorders. However, as both neuronal and non-neuronal cells express chemokine receptors in the CNS, it is unclear to what extent cell type-specific receptors mediate the effects of chemokines on neurons. There is also controversy about the possibility that chemokines may be beneficial or toxic for neurons in various physiological and pathological conditions, their action being affected by the activity of other endogenous systems, such as those for opioids. Our research aims to determine the direct effects of chemokines on neurons independently of their action on inflammatory and glial cells, and identify the molecular mechanisms that regulate the activity of neuronal chemokine receptors including their interaction with major neurotransmitter and neuropeptide systems. This application will study the involvement of neuronal chemokine receptors in the survival of pure populations of rat and human neurons. The hypothesis suggested by our preliminary data is that these receptors play an important role in supporting neuronal survival and that their abnormal activation results in neuronal death. To test this hypothesis, the question of whether individual chemokine receptors (i.e. CXCR4) may couple to both neurotrophic and neurotoxic pathways will be addressed first. To this end, the interaction of neuronal CXCR4 with the neurotoxic HIV-1 protein gp120 will also be studied. Thus, the ability of chemokines and gp120 to induce receptor phosphorylation, dimerization and desensitization in various experimental conditions will be investigated. Differences in the molecular activation/deactivation of chemokine receptors, upon binding to chemokines and gp120 will be examined, to evaluate whether this may lead to recruitment of different effectors with opposite results on neuronal survival. Finally, the modulation of chemokine receptor function and expression by glutamate and opioids will be studied, to test the possibility that an alternative or additional level of regulation is exerted by the simultaneous activation of these systems, altering the effect of chemokines on neuronal signaling and survival. Biochemical, molecular biological, pharmacological and imaging approaches will be employed to study the activation of chemokine receptors and test their effect on the intracellular pathways involved in neuronal survival and apoptosis. These studies will help us understand the physiological role of chemokines in the CNS and their involvement in HIV neuropathology, neuroinflammatory diseases as well as in the neuropathology associated to drug abuse.