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：
8245166
负责人：
Johnny J He
金额：
$ 44.07万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245166
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. PUBLIC HEALTH RELEVANCE: HIV-1 infection often causes a number of brain diseases and affects the ability of people to care for themselves and thus the quality of their daily life. The social and economic impact cannot be overemphasized. The current study seeks to have a better understanding of the host factors that are important for the disease progression and then use the knowledge acquired to develop new markers to monitor the disease progression and treatment response and develop new therapeutics.

描述（由申请人提供）：大多数 AIDS 患者都会发生中枢神经系统 (CNS) 的 HIV-1 感染，并导致各种神经功能障碍和神经病理学，通常称为神经艾滋病。小胶质细胞/巨噬细胞和星形胶质细胞在一定程度上是中枢神经系统中 HIV-1 感染的主要靶细胞，而神经元很少被 HIV-1 感染，但大多数在 HIV/神经艾滋病中受到影响。因此，人们提出了几种HIV/神经艾滋病发病机制的间接机制。其中包括 HIV-1 Tat 蛋白。我们已经证明，在没有 HIV-1 感染的情况下，Tat 表达足以引起神经行为异常和病理，与 HIV/神经艾滋病中注意到的大多数相似。此外，我们还发现 Tat 激活星形胶质细胞中的胶质纤维酸性蛋白（GFAP）表达，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，并与星形胶质细胞中的 GFAP 聚集和内质网 (ER) 应激以及神经元存活受损有关。重要的是，我们还获得了初步证据，证明脑脊液 (CSF) 水平与 HIV/神经艾滋病发病机制有关。作为我们研究的逻辑延伸，我们建议进一步剖析 GFAP 在 Tat 神经毒性和 HIV/神经艾滋病发病机制中的功能。此外，我们将确定使用脑脊液 GFAP 水平作为新型 HIV/神经艾滋病生物标志物的可行性。因此，当前提议的基本假设是 Tat 通过 GFAP 激活/聚集和 ER 应激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Tat神经毒性和HIV/神经艾滋病发病机制的介质，也是一个指标。为了检验这一假设，我们建议解决以下相互关联的具体目标：（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应激对星形胶质细胞的影响； (3) 明确GFAP-/ER应激介导的神经毒性的分子机制； (4) 研究使用 GFAP 作为新型 HIV/神经艾滋病生物标志物的潜力。我们将采用分子、细胞、生化和遗传学相结合的方法，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、原代人胎儿脑培养物、包埋脑组织和脑脊液我们研究中的一个大型 HIV-1 队列的样本。寻求的答案对于理解这种关键且普遍的蛋白质 GFAP 及其在 HIV/神经艾滋病发病机制中的作用具有根本意义。此外，这些答案还应有助于识别艾滋病毒/神经艾滋病生物标志物和制定抗艾滋病毒/神经艾滋病治疗策略。公共卫生相关性：HIV-1 感染通常会导致多种脑部疾病，并影响人们照顾自己的能力，从而影响他们的日常生活质量。社会和经济影响怎么强调都不为过。目前的研究旨在更好地了解对疾病进展重要的宿主因素，然后利用所获得的知识开发新的标记物来监测疾病进展和治疗反应并开发新的疗法。