NEUROTOXIC MECHANISMS MEDIATED BY LENTIVIRUS-INDUCED PROTEOLYSIS

描述（由申请人提供）：神经元被HIV-1感染破坏，导致hiv相关痴呆的机制尚不清楚。我们最近的研究表明，神经元通过一种新的死亡信号通路被HIV-1杀死，从而导致神经元凋亡和神经变性。在这一途径中，从hiv感染或活化的巨噬细胞中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）是高度神经毒性的，通过假定的G蛋白偶联受体起作用。我们的研究还表明，C-SDF也诱导单核细胞而非星形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症分子（C-SDF），导致神经元凋亡，由一种新的细胞膜受体介导，引发不同的反应表型。因此，本提案的总体目标是确定sdf衍生的神经毒性和神经炎症配体的分子结构和丰度，并表征其同源受体，以描绘神经元被C-SDF杀死的分子机制。我们将描述C-SDF的相对表达，并定义C-SDF免疫反应蛋白与hiv相关痴呆的分子结构。C- SDF内的比较分子结构域将根据其神经毒性和神经炎症特性进行定义。C-SDF受体将通过配体结合研究和序列测定来表征。神经元和单核细胞中C- SDF受体的反应谱将被表征，使我们能够制定合理的hiv相关痴呆的诊断和治疗策略。概要：艾滋病毒相关的脑部疾病是一个全球性的公共卫生问题，它也预示着艾滋病毒感染期间存活率的降低。本文提出的研究将定义宿主蛋白的机制，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。从这项建议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.