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

• 批准号: 8098194
• 负责人: Johnny J He
• 金额: $ 6.91万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098194
• 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

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）：HIV-1中枢神经系统（CNS）感染发生在大多数艾滋病患者中，引起各种神经功能障碍和神经病理，通常被称为神经艾滋病。在中枢神经系统中，小胶质细胞/巨噬细胞和星形胶质细胞是HIV-1感染的主要靶细胞，而神经元很少被HIV-1感染，但主要在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的表达足以引起神经行为异常和与大多数HIV/神经艾滋病相似的病理。此外，我们已经证明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，我们还获得了将脑脊液（CSF）水平与HIV/神经艾滋病发病机制联系起来的初步证据。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CSF GFAP水平作为一种新的HIV/神经艾滋病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/聚集和内质网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不仅是一个中介，而且是Tat神经毒性和HIV/神经艾滋病发病机制的一个指标。为了验证这一假设，我们提出解决以下相关的具体目标：(1)表征星形胶质细胞中GFAP表达与内质网应激之间的关系；(2)探讨tat激活GFAP表达/聚集及内质网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GFAP作为新型HIV/神经艾滋病生物标志物的潜力。在我们的研究中，我们将使用分子、细胞、生化和遗传相结合的方法，包括使用原代小鼠皮质星形胶质细胞培养和神经元培养、Tat转基因小鼠、gmap -null/Tat转基因小鼠、原代人类胎儿脑培养、嵌入的脑组织和大型HIV-1队列的CSF样本。所寻求的答案对于理解这种关键和普遍存在的蛋白质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，这些答案也将有助于识别艾滋病毒/神经艾滋病生物标志物和开发抗艾滋病毒/神经艾滋病治疗策略。