GFAP as a novel HIV/neuroAIDS biomarker

GFAP 作为一种新型 HIV/神经艾滋病生物标志物

基本信息

批准号：
8644917
负责人：
Johnny J He
金额：
$ 47.56万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644917
关键词：
AIDS Dementia Complex AIDS neuropathy Acquired Immunodeficiency Syndrome Address Affect Agreement Astrocytes Astrocytosis Biochemical Biochemical Genetics Biological Markers Blood - brain barrier anatomy Brain Brain Diseases CCL2 gene CD4 Positive T Lymphocytes CXCL10 gene Calcium Caring Categories Cells Central Nervous System Infections Cerebrospinal Fluid Cessation of life Cognitive Development Disease Disease Progression Endoplasmic Reticulum Fascicle Functional disorder Gene Expression Genetic Transcription Giant Cells Glial Fibrillary Acidic Protein Goals HIV HIV Infections HIV-1 Highly Active Antiretroviral Therapy Homeostasis Human Impaired cognition Individual Infection Injection of therapeutic agent Integration Host Factors Interleukin-1 Interleukin-6 Journals Knowledge Laboratories Life Link Lymphocyte Mediating Mediator of activation protein Microglia Minor Molecular Molecular Profiling Monitor Motor Mus Myelin Nerve Degeneration Neuraxis Neuroglia Neurologic Neurologic Dysfunctions Neurons Pallor Pathogenesis Pathology Patients Pharmacology Process Property Proteins Recruitment Activity Resources Role Sampling Signal Transduction Social Impacts Staging Symptoms Testing Therapeutic Transgenic Mice Viral antiretroviral therapy biological adaptation to stress brain cell brain tissue cerebral atrophy chemokine cohort cytokine economic impact endoplasmic reticulum stress fetal immune activation macrophage monocyte motor disorder neurobehavioral neuron apoptosis neuronal survival neuropathology neurotoxicity novel novel marker novel therapeutics prevent protein activation protein aggregate protein aggregation protein expression protein function public health relevance tat Protein transcription factor treatment response

项目摘要

DESCRIPTION (provided by applicant): HIV-1 infection of the central nervous system (CNS) occurs in a majority of AIDS patients and causes a variety of neurologic dysfunction and neuropathologies generally termed neuroAIDS. Microglia/macrophages, and astrocytes to a less extent are the main target cells for HIV-1 infection in the CNS, whereas neurons are rarely infected by HIV-1 but mostly affected in HIV/neuroAIDS. Therefore, several indirect mechanisms have been proposed for HIV/neuroAIDS pathogenesis. Among them is HIV-1 Tat protein. We have shown that Tat expression in the absence of HIV-1 infection is sufficient to cause neurobehavioral abnormalities and pathologies similar to most of those noted in HIV/neuroAIDS. Moreover, we have shown that Tat activates glial fibrillary acidic protein (GFAP) expression in astrocytes and results in astrocyte dysfunction and subsequent neuron death. Furthermore, our preliminary studies have found that Tat-activated GFAP expression involves a network of transcription factors and is associated with GFAP aggregates and endoplasmic reticulum (ER) stress in astrocytes and impaired neuron survival. Importantly, we have also obtained preliminary evidence to link the cerebrospinal fluid (CSF) levels to HIV/neuroAIDS pathogenesis. As a logical extension of our studies, we propose to further dissect the GFAP function in Tat neurotoxicity and HIV/neuroAIDS pathogenesis. Besides, we will determine the feasibility of using the CSF GFAP level as a novel HIV/neuroAIDS biomarker. Thus, the underlying hypothesis for the current proposal is that Tat adversely affects astrocyte function and neuronal survival through GFAP activation/aggregation and ER stress. In other words, GFAP is not only a mediator but also an indicator of Tat neurotoxicity and HIV/neuroAIDS pathogenesis. To test this hypothesis, we propose to address the following interrelated specific aims: (1) To characterize the relationship between GFAP expression and ER stress in astrocytes; (2) To determine effects of Tat-activated GFAP expression/aggregation and ER stress on astrocytes; (3) To define the molecular mechanisms of GFAP-/ER stress-mediated neurotoxicity; and (4) To investigate the potential of using GFAP as a novel HIV/neuroAIDS biomarker. We will use a combined molecular, cellular, biochemical, and genetic approach, including use of primary mouse cortical astrocyte cultures and neuron cultures, Tat transgenic mice, GFAP-null/Tat transgenic mice, primary human fetal brain cultures, embedded brain tissues and CSF samples of a large HIV-1 cohort in our studies. The answers sought have fundamental significance for understanding of this critical and pervasive protein GFAP, and its role in HIV/neuroAIDS pathogenesis. In addition, these answers shall also aid in identification of HIV/neuroAIDS biomarkers and development of anti-HIV/neuroAIDS therapeutic strategies.

描述（由申请人提供）：中枢神经系统（CNS）的HIV-1感染发生在大多数艾滋病患者中，并引起多种神经功能障碍和神经病理学通常称为神经助理。小胶质细胞/巨噬细胞和星形胶质细胞在较小程度上是中枢神经系统中HIV-1感染的主要靶细胞，而神经元很少受HIV-1感染，但大多在HIV/神经辅助中受到影响。因此，已经提出了几种用于HIV/神经辅助发病机理的间接机制。其中包括HIV-1 TAT蛋白。我们已经表明，在没有HIV-1感染的情况下，TAT表达足以引起与HIV/神经助剂中大多数人相似的神经行为异常和病理。此外，我们已经表明，TAT激活星形胶质细胞中的神经胶质原纤维酸性蛋白（GFAP）表达，并导致星形胶质细胞功能障碍和随后的神经元死亡。此外，我们的初步研究发现，TAT激活的GFAP表达涉及转录因子网络，并且与星形胶质细胞中的GFAP聚集体和内质网应力（ER）相关，并且神经元存活受损。重要的是，我们还获得了初步证据，以将脑脊液（CSF）水平与HIV/神经辅助发病机理联系起来。作为我们研究的逻辑扩展，我们建议进一步剖析TAT神经毒性和HIV/神经辅助发病机理中的GFAP功能。此外，我们将确定将CSF GFAP水平用作新型HIV/神经辅助生物标志物的可行性。因此，当前建议的基本假设是，TAT通过GFAP激活/聚集和ER应力对星形胶质细胞功能和神经元存活产生不利影响。换句话说，GFAP不仅是介体，而且是TAT神经毒性和HIV/神经辅助发病机理的指标。为了检验这一假设，我们建议解决以下相互关联的特定目的：（1）表征星形胶质细胞中GFAP表达与ER应激之间的关系；（2）确定TAT激活的GFAP表达/聚集和ER应力对星形胶质细胞的影响；（3）定义GFAP-/ER应力介导的神经毒性的分子机制；（4）研究使用GFAP作为新型HIV/神经辅助生物标志物的潜力。我们将使用分子，细胞，生化和遗传方法的组合，包括使用原代小鼠皮质星形胶质细胞培养物和神经元培养物，TAT转基因小鼠，GFAP-NULL/TAT转基因小鼠，原发性人类胎儿脑培养，嵌入了HIV-1 COLHORT的大型HIV-1 Colehort中的脑组织和CSF样本。寻求的答案对于理解这种关键和普遍的蛋白质GFAP及其在HIV/神经辅助发病机理中的作用具有基本意义。此外，这些答案还应有助于识别艾滋病毒/神经助剂生物标志物以及抗HIV/神经辅助治疗策略的发展。