HIV NEUROPATHY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 随着近年来HIV相关痴呆发病率的下降，HIV相关感觉神经病变（HIV-SN）是与AIDS相关的最常见的神经系统疾病。它影响高达30%的患者，并与晚期HIV疾病和双脱氧甘草酸苷药物有关。迄今为止，研究工作主要集中在成年患者身上，尚不清楚儿童是否容易受到这种并发症的影响。HIV-SN的病理生理学机制尚不明确。我们的基本假设是，艾滋病的症状性神经病变是通过放大预先存在的神经损伤而发展的。HIV诱导的免疫失调与局部巨噬细胞活化起着关键作用。我们提出了一个前瞻性和纵向研究周围神经病变的西班牙裔队列的儿童和成人艾滋病毒感染的患者来解决这些问题。拟议研究的基本原理集中在这样一个事实上，即关于特定年龄或种族人群神经病决定因素的信息非常有限，这些信息应有助于实施具体有效的治疗或预防策略。为了实现本申请的目的，我们计划追求以下具体目标：1）比较HIV血清阳性儿童和成人队列中感觉神经病的发病率和决定因素。2)通过测量PBMC中磷酸化核苷类似物的细胞内浓度，确定核苷类似物代谢与周围神经病变之间的相关性。3)目的探讨巨噬细胞功能失调、免疫激活与感觉神经病变的关系。4)确定HIV感觉神经病中免疫激活和外周神经损伤的模式如何影响脊髓背角的重塑以及与背根神经节疼痛相关的分子通路。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. With recent declines in the incidence rates of HIV-associated dementia, HIV-associated sensory neuropathy (HIV-SN) is the commonest of the neurological disorders associated with AIDS. It affects up to 30% of patients and is associated with advanced HIV disease, and with dideoxymicleoside agents. To date research efforts have focused on adult patients, and it is unclear whether children are vulnerable to this complication. The pathophysiological mechanisms, which underlie HIV-SN remain undefined. Our underlying hypothesis is that symptomatic neuropathy in AIDS develops through the magnification of pre-existing nerve damage. HIV-induced immune dysregulation with local macrophage activation plays a critical role. We propose a prospective and longitudinal study of peripheral neuropathy in a Hispanic cohort of pediatric and adult HIV-Infected patients to address these questions. The rationale for the proposed study centers on the fact that there is very limited information about determinants of neuropathy in specific age or ethnic groups and this information should pen-nit the implementation of specific and effective therapeutic or preventive strategies. To accomplish the objectives of this application we plan to pursue the following specific aims: 1) To compare the incidence rates and determinants of sensory neuropathy in cohorts of HIV seropositive children and adults. 2) To determine the association between nucleoside analogue metabolism and peripheral neuropathy by measuring intracellular concentrations of phosphorylated nucleoside analogues in PBMCs. 3) To determine the relationship between macrophage dysregulation, immune activation and the development of sensory neuropathy. 4) To determinate how the patterns of immune activation and peripheral nerve damage in HIV sensory neuropathy affect the remodeling of the dorsal horn of the spinal cord and molecular pathways associated with pain in the dorsal root ganglia.