NEUROTOXIC MECHANISMS MEDIATED BY LENTIVIRUS-INDUCED PROTEOLYSIS

描述(申请人提供)：艾滋病毒-1感染损伤神经元，导致艾滋病毒相关性痴呆的机制(S)仍未解决。我们最近发现，HIV-1通过一种新的死亡信号通路杀死神经元，导致神经元凋亡和神经变性。在这一途径中，由HIV感染或激活的巨噬细胞释放的基质金属蛋白酶-2可裂解趋化因子基质细胞衍生因子(SDF)-1。裂解的SDF-1(C-SDF)具有高度的神经毒性，可能通过G蛋白偶联受体发挥作用。我们的研究还表明，C-SDF也能诱导单核细胞致炎基因的表达，但不能诱导星形胶质细胞表达致炎基因。我们的工作假设是SDF-1的蛋白水解性裂解导致一种高度神经毒性和神经炎性分子(C-SDF)，它由一种新的细胞膜受体介导，引发不同的反应表型，从而导致神经元凋亡。因此，这项建议的首要目标是确定SDF衍生的神经毒性和神经炎性配体的分子结构和丰度，并描述其同源受体的特征，长期目标是描述C-SDF杀死神经元的分子机制。我们将表征C-SDF的相对表达，并确定与HIV相关痴呆相关的C-SDF免疫反应蛋白的分子结构。C-SDF中的比较分子结构域将根据它们的神经毒性和神经炎性来定义。C-SDF受体(S)将通过配基结合研究和序列测定来表征。C-SDF受体(S)在神经元和单核细胞中的反应谱将被描述，使我们能够开发出合理的艾滋病毒相关性痴呆的诊断和治疗策略。总结：与艾滋病毒相关的脑部疾病是一个全球性的公共卫生问题，这也预示着艾滋病毒感染期间存活率的下降。这里提出的研究将确定大脑中的宿主蛋白质-基质细胞衍生因子-1因HIV感染而降解的机制，从而产生一种高度神经毒性的分子。从这项提案中得出的信息将适用于艾滋病毒相关脑部疾病的预防和治疗。

DESCRIPTION (provided by applicant): The mechanism(s) by which neurons are damaged by HIV-1 infection, leading to HIV-associated dementia remain unresolved. We have recently shown that neurons are killed by HIV-1 through a novel death- signaling pathway, which leads to neuronal apoptosis and neurodegeneration. In this pathway, matrix metalloproteinase (MMP)-2, released from HIV-infected or -activated macrophages, cleaves the chemokine, stromal cell-derived factor (SDF)-1. Cleaved SDF-1 (C-SDF) is highly neurotoxic, acting via a putative G protein-coupled receptor. Our studies also show that C-SDF also induces expression of pro-inflammatory genes in monocytoid but not astrocytic cells. Our working hypothesis is that proteolytic cleavage of SDF-1 results in a highly neurotoxic and neuro-inflammatory molecule (C-SDF), which causes neuronal apoptosis, mediated by a novel cell membrane receptor that triggers a distinct response phenotype. Thus, the overarching objective of this proposal is to define the molecular structure and abundance of the SDF-derived neurotoxic and neuro-inflammatory ligand and to characterize its cognate receptor with the long-term objective of delineating the molecular mechanisms by which neurons are killed by C-SDF. We will characterize the relative expression of C-SDF together with defining the molecular structures of the C-SDF immunoreactive protein in relation to HIV-associated dementia. Comparative molecular domains within C- SDF will be defined in terms of their neurotoxic and neuroinflammatory properties. The C-SDF receptor(s) will be characterized by ligand binding studies and sequence determination. The response profiles of the C- SDF receptor(s) in neurons and monocytoid cells will be characterized, permitting us to develop rational diagnostic and therapeutic strategies for HIV-associated dementia. Lay Summary: HIV-associated brain disease represents a global public health problem, which also heralds reduced survival during HIV infection. The studies proposed herein will define the mechanisms by which a host protein, stromal cell-derived factor-1, in the brain is degraded by HIV infection, resulting in a highly neurotoxic molecule. The information derived from this proposal will be applicable to the prevention and treatment of HIV-associated brain disease.