HIV-1-Related Peripheral Sensory Neuropathy

描述（由申请人提供）：HIV-1病毒感染与中枢和周围神经系统的影响有关，包括HIV-1认知/运动综合征和HIV-1相关的感觉神经病变。在这项拨款申请中，我们将研究HIV-1病毒损害与疼痛相关的感觉神经元功能的机制。在我们的初步数据中，我们证明感觉（背根神经节，[DRG]）神经元表达CXCR4以及其他趋化因子受体。趋化因子或HIV-1外壳蛋白gpl20激活这些受体可激活细胞内信号通路，产生神经元兴奋和疼痛。Gp120还激活JNK信号通路，最终导致神经元凋亡死亡。在本提案中讨论的实验中，我们将(1)进一步研究CXCR4和其他受体在介导gp120对DRG神经元的影响中的作用；(2)研究趋化因子、gpl20、抗逆转录病毒药物和JNK信号通路成员在影响感觉神经元功能中的相互作用；(3)研究gpl20激活JNK并诱导DRG神经元死亡的机制。这些结果将有助于我们了解HIV-1病毒如何损害感觉神经元的功能，并为治疗HIV-1相关感觉神经病变提供新的治疗干预靶点。

DESCRIPTION (provided by applicant): Infection with the HIV-1 virus is associated with effects on both the central and peripheral nervous systems including the HIV-1 cognitive/motor syndrome and HIV-1 -related sensory neuropathies. In this grant proposal we shall investigate the mechanisms by which the HIV-1 virus can compromise the function of sensory neurons associated with pain. In our preliminary data we demonstrate that sensory (dorsal root ganglion, [DRG]) neurons express the CXCR4 as well as other chemokine receptors. Activation of these receptors by chemokines or by the HIV-1 coat protein gpl20 activates intracellular signaling pathways that produce neuronal excitation and pain. Gp120 also activates the JNK signaling pathway that ultimately produces neuronal apoptotic death. In the experiments discussed in this proposal we shall (1) further examine the role of the CXCR4 and other receptors in mediating the effects of gp120 on DRG neurons; (2) examine the interactions between chemokines, gpl20, anti-retroviral drugs and members of the JNK signaling pathway in compromising the function of sensory neurons; and (3) examine the mechanisms by which gpl20 produces activation of JNK and induces the death of DRG neurons. These results will help us to understand how the HIV-1 virus can compromise the functions of sensory neurons and suggest novel targets for therapeutic interventions in the treatment of HIV-1 -associated sensory neuropathies.