NEUROTOXIC MECHANISMS MEDIATED BY LENTIVIRUS-INDUCED PROTEOLYSIS

描述（由申请人提供）：HIV-1感染导致神经元受损，导致HIV相关痴呆的机制尚未解决。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。在该途径中，从HIV感染或活化的巨噬细胞释放的基质金属蛋白酶（MMP）-2切割趋化因子，基质细胞衍生因子（SDF）-1。裂解的SDF-1（C-SDF）具有高度神经毒性，通过假定的G蛋白偶联受体发挥作用。我们的研究还表明，C-SDF还诱导单核细胞样细胞而不是星形胶质细胞中促炎基因的表达。我们的工作假设是SDF-1的蛋白水解裂解导致高度神经毒性和神经炎性分子（C-SDF），其引起神经元凋亡，由触发不同反应表型的新型细胞膜受体介导。因此，该提案的首要目标是定义SDF衍生的神经毒性和神经炎性配体的分子结构和丰度，并表征其同源受体，其长期目标是描绘C-SDF杀死神经元的分子机制。我们将描述C-SDF的相对表达，并定义与HIV相关痴呆相关的C-SDF免疫反应蛋白的分子结构。C-SDF内的比较分子结构域将根据其神经毒性和神经炎性特性来定义。将通过配体结合研究和序列测定表征C-SDF受体。神经元和单核细胞样细胞中C-SDF受体的反应谱将被表征，使我们能够开发合理的诊断和治疗HIV相关性痴呆的策略。艾滋病毒相关的脑部疾病代表了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生存率的降低。本文提出的研究将定义宿主蛋白质，基质细胞衍生因子-1，在大脑中被HIV感染降解，导致高度神经毒性分子的机制。从该提案中获得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.