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Modulation of Cystatins and Cathepsins in HIV-1 Neuropathogenesis

半胱氨酸蛋白酶抑制剂和组织蛋白酶在 HIV-1 神经发病机制中的调节

基本信息

批准号：
7880910
负责人：
LOYDA M MELENDEZ
金额：
$ 50.05万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880910
关键词：
Adenovirus Vector Affect Antibodies Antiviral Therapy Apoptotic Behavioral Biological Markers Brain Bromodeoxyuridine Cathepsins Cathepsins B Cells Cellular Structures Cerebrospinal Fluid Cognitive Cystatins Diagnosis Disease Effector Cell Enzyme-Linked Immunosorbent Assay Gene Expression Gene Proteins Glycogen Synthase Kinases Goals HIV HIV Infections HIV encephalitis HIV-1 Highly Active Antiretroviral Therapy Hispanics Immune Impaired cognition Impairment Infection Inflammatory Knock-out Knowledge Laboratories Liquid substance Maintenance Measures Microglia Molecular Molecular Probes Molecular Profiling Mononuclear Motor NF-kappa B National NeuroAids Tissue Consortium Nebraska Nerve Degeneration Neurocognitive Neurons Neuropathogenesis Nitric Oxide Oxidation-Reduction Oxidative Stress Pathway interactions Phagocytes Phenotype Plasma Play Predictive Value Process Production Proteins Proteomics Reactive Oxygen Species Reporting Role Sampling Small Interfering RNA Source Specimen Superoxides TdT-Mediated dUTP Nick End Labeling Assay Testing Up-Regulation Viral Viral Load result Virus Western Blotting Woman antiretroviral therapy brain tissue cognitive function cohort in vivo macrophage monocyte neurotoxic neurotoxicity novel post gamma-globulins protein expression research study response stefin

项目摘要

DESCRIPTION (provided by applicant): Modulation of cystatins and cathepsins in the neuropathogenesis of HIV-1 infection Cognitive impairment (CI) occurs during advanced HIV-1 infection, despite antiretroviral therapy (HAART). The molecular and cellular mechanisms for neuronal impairment evolve from neurotoxic secretory products produced from mononuclear phagocytes (MP; perivascular macrophages and microglia). Although the intracellular mechanisms that affect toxic MP secretions are incompletely known, the effector cell responses do play a pivotal role in CI. The long-term goal of the proposed study is to provide a better understanding of the role of macrophage secretory factors in homeostatic control during progressive HIV infection of the brain and to uncover novel targets for potential therapies. Among many secretory factors, cystatins and cathepsins secreted by MP play broad yet important roles in neuroregulatory responses. In particular, our laboratory and ex vivo experiments have shown the presence of cathepsins, cystatins, and SOD in virus-infected MP culture fluids and cerebrospinal fluid (CSF) of HIV-seropositive women with CI by proteomic analyses. Nevertheless, their role in neurodegenerative processes is not completely understood. The proposed study will elucidate the role played by cystatins and cathepsins, and SOD, on HIV-infected macrophages and their interactions with neuronal cells, which is critical for controlling the pro-inflammatory microenvironment in the brain during the induction of CI. We hypothesize that dysregulation of cystatins in HIV-infected macrophages during oxidative stress promotes cathepsin-B induced neurotoxicity and therefore contributes to CI. We will test this hypothesis with the following specific aims: 1) To determine, by analysis of gene and protein expression, how the interplay between cystatin B and cathepsin B regulates HIV-1 infection in macrophages and affects neurotoxic phenotype; 2) To define the roles of cystatin B/C, cathepsin B, SOD, and proteins affected by their deregulation, found in Aim 1, as predictors of progression to CI in the presence of HAART. The significance and long-term implication of this study is that it will fill the gaps in knowledge regarding the interactions between cystatins, cathepsins and SOD in macrophages and their role in neuropathogenesis. The studies with the Hispanic cohort will also clarify the role of cystatins, cathepsins, and SOD in HIV-cognitive impairment in the post-HAART era. The proposed studies will determine the role of macrophage cystatins, cathepsins, SOD, and the proteins affected by their deregulation in HIV replication and neurotoxicity. The Hispanic cohort of HIV-infected women characterized for cognitive function and under antiviral therapy is an excellent source for the study of these possible biomarkers in the HAART era. The CSF, plasma, monocyte, and macrophage samples derived from this cohort have been stored longitudinally and provide an important source for testing our hypothesis: that over expression of cystatins in HIV-infected macrophages will promote cathepsin B-induced neurotoxicity and therefore contribute to CI. This study may elucidate novel targets for diagnosis and therapy.

描述（由申请人提供）：半胱氨酸蛋白酶抑制剂和组织蛋白酶在HIV-1感染的神经发病机制中的调节尽管进行了抗逆转录病毒治疗（HAART），但在晚期HIV-1感染期间仍发生认知障碍（CI）。神经元损伤的分子和细胞机制从单核吞噬细胞（MP;血管周围巨噬细胞和小胶质细胞）产生的神经毒性分泌产物演变而来。虽然影响毒性MP分泌的细胞内机制尚不完全清楚，但效应细胞反应在CI中确实起着关键作用。这项研究的长期目标是更好地了解巨噬细胞分泌因子在进行性HIV感染大脑过程中的稳态控制作用，并发现潜在治疗的新靶点。在众多的分泌因子中，MP分泌的半胱氨酸蛋白酶抑制剂和组织蛋白酶在神经调节反应中起着广泛而重要的作用。特别是，我们的实验室和离体实验表明，存在组织蛋白酶，半胱氨酸蛋白酶抑制剂，和SOD病毒感染的MP培养液和脑脊液（CSF）的HIV血清阳性的妇女CI蛋白质组学分析。然而，它们在神经退行性过程中的作用尚未完全了解。拟议的研究将阐明半胱氨酸蛋白酶抑制剂和组织蛋白酶以及SOD对HIV感染的巨噬细胞及其与神经元细胞的相互作用所起的作用，这对于在CI诱导期间控制脑中的促炎微环境至关重要。我们推测，在HIV感染的巨噬细胞在氧化应激过程中，胱抑素的失调促进组织蛋白酶B诱导的神经毒性，因此有助于CI。我们将通过以下具体目标来验证这一假设：1）通过分析基因和蛋白表达，确定胱抑素B和组织蛋白酶B之间的相互作用如何调节巨噬细胞中的HIV-1感染并影响神经毒性表型; 2）明确半胱氨酸蛋白酶抑制剂B/C、组织蛋白酶B、SOD及其失调影响的蛋白质的作用，发现在Aim 1中，作为HAART治疗进展为CI的预测因子。这项研究的意义和长期意义在于，它将填补有关巨噬细胞中半胱氨酸蛋白酶抑制剂，组织蛋白酶和SOD之间的相互作用及其在神经发病机制中的作用的知识空白。西班牙裔队列研究还将阐明半胱氨酸蛋白酶抑制剂、组织蛋白酶和SOD在HAART后时代HIV认知障碍中的作用。拟议的研究将确定巨噬细胞半胱氨酸蛋白酶抑制剂，组织蛋白酶，超氧化物歧化酶的作用，和蛋白质的影响，他们在艾滋病毒复制和神经毒性的失调。以认知功能为特征并接受抗病毒治疗的西班牙裔HIV感染妇女队列是HAART时代研究这些可能的生物标志物的极好来源。来自该队列的CSF、血浆、单核细胞和巨噬细胞样本已纵向储存，并为检验我们的假设提供了重要来源：HIV感染的巨噬细胞中半胱氨酸蛋白酶抑制剂的过度表达将促进组织蛋白酶B诱导的神经毒性，因此有助于CI。这项研究可能会阐明新的诊断和治疗的目标。