HIV-1-Related Peripheral Sensory Neuropathy

描述（由申请方提供）：HIV-1病毒感染对中枢和外周神经系统的影响相关，包括HIV-1认知/运动综合征和HIV-1相关感觉神经病。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CXCR 4以及其他趋化因子受体。通过趋化因子或通过HIV-1外壳蛋白gp 120激活这些受体激活产生神经元兴奋和疼痛的细胞内信号传导途径。Gp 120还激活JNK信号通路，最终导致神经元凋亡性死亡。在本实验中，我们将（1）进一步研究CXCR 4和其他受体在介导gp 120对DRG神经元的作用中的作用;（2）研究趋化因子、gp 120、抗逆转录病毒药物和JNK信号通路成员在损害感觉神经元功能中的相互作用;（3）研究gp 120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相关感觉神经病变的治疗干预提供新的靶点。

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.