Overexpression of Complement in the Brain and HIV Neuropathogenesis

大脑中补体的过度表达与 HIV 神经发病机制

• 批准号: 7687234
• 负责人: DAVID J VOLSKY
• 金额: $ 20.33万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687234
• 关键词: AIDS Dementia Complex; Address; Animal Model; Animals; Astrocytes; Brain; Cell Death; Cells; Complement; Complement 1q; Complement 3a; Data; Deposition; Development; Discipline; Disease; Functional disorder; HIV; HIV Infections; HIV-1; Human; Incidence; Infection; Interleukin-6; Investigation; Knock-out; Knockout Mice; Learning; Mediating; Mediator of activation protein; Molecular Biology; Mus; Nerve Degeneration; Nervous system structure; Neurobiology; Neurocognitive; Neurodegenerative Disorders; Neurons; Neuropathogenesis; New York; Pathway interactions; Process; Production; Public Health; Research; Retrovirology; Role; Route; Scourge; Serum Proteins; Synapses; System; Testing; Translational Research; Transplantation; United States; Work; base; complement C3 precursor; functional disability; mouse model; neuropathology; overexpression; pandemic disease; public health relevance; research study; tool

DESCRIPTION (provided by applicant): Complement components are elevated in the brain in a variety of neurodegenerative disorders but their contribution to neuropathogenesis is unknown. Recent studies indicate that C1q and C3 contribute to synaptic remodeling during development and mediate some specific forms of synaptic damage during disease. Consistent with these findings, we have shown that C3 is elevated a) in the brain during HIV-1-associated dementia; b) in mice infected with chimeric HIV-1; and c) in primary human and mouse astrocytes exposed to HIV-1 in culture. Our preliminary data also indicate that HIV-1 induces C3 in astrocytes indirectly through a NF-:B dependent pathway that correlates with production of interleukin 6 (IL-6). Based on the finding that synaptic remodeling during normal brain development requires C3, we hypothesize that C3 overexpression in the brain during HIV infection initiates ectopic synaptic remodeling and neuropathogenesis. In this application, we propose exploratory studies toward testing this hypothesis in two Specific Aims: 1. We will determine the mechanism of C3 induction in astrocytes by intact HIV-1 and Tat with focus on the potential role of HIV-1-induced IL-6 as a mediator. 2. We will identify a mouse model of HIV-1-associated neuropathogenesis that is most suitable for study of C3 and IL-6 induction by HIV-1 or Tat in the brain and the deposition of activated complement in synapses. The proposed exploratory studies should establish the conceptual basis and experimental tools for detailed investigation of the role of complement and its potential inducers HIV and IL-6 in HIV mediated neuropathogenesis. The studies will include experiments with HIV and Tat in primary astrocytes in culture and will evaluate three existing small animal models of HIV neuropathogenesis including transplant of HIV-1-infected syngeneic astrocytes into the mouse brain, transplant of Tat-expressing syngeneic astrocytes into the mouse brain, and direct infection of mice by chimeric HIV-1. Each system will employ wildtype, C3 knockout, and IL-6 knockout mice. Research disciplines involved in this project include retrovirology, molecular biology, neurobiology, neuropathology, and animal studies. The project addresses the growing public health problem of HIV-associated neurocognitive disorders. If successful, the small animal models characterized in this work may be employed for translational research on treatments designated to counter the potential neurodegenerative actions of complement and IL-6 in the brain. PUBLIC HEALTH RELEVANCE: HIV-1 infection continues as a world-wide pandemic. It is disturbing to learn that the incidence of new infections has been under-estimated in the United States and the rate is actually increasing over recent years in New York. Thus this scourge remains a serious Public Health challenge. This application addresses one disorder that persists among HIV-1-infected people, neurocognitive disorders. Nervous system dysfunction can arise from outright cell death, but recent studies also indicate the importance of neuronal functional impairment in the HIV-1- infected brain. This application focuses upon a mechanism of synapse elimination that normally takes place in the developing brain, but may be subverted during HIV-1 infection. This route entails expression of complement component C3, a serum protein found elevated in the brain during HIV-1 infection, as shown here. Proposed are studies on the mechanism of overexpression in primary astrocytes, the most numerous cell in the brain. Turning to understand the impact of this process in the brain, three mouse models of HIV-1 neuropathogenesis will be investigated for the salience of C3 expression and synaptic elimination, a clear path to neurodegeneration. If successful, this developmental application will provide significant leads to counter a new, physiologically relevant pathway of functional impairment of neurons that occurs during HIV-1 infection.

描述（由申请人提供）：在多种神经退行性疾病中，大脑中的补体成分升高，但它们对神经发病的贡献尚不清楚。最近的研究表明，C1Q和C3在发育过程中有助于突触重塑，并介导疾病期间某些特定形式的突触损伤。与这些发现一致，我们已经表明，在HIV-1相关痴呆症中，C3升高了a）大脑中的a）。 b）在感染嵌合HIV-1的小鼠中； c）在培养中暴露于HIV-1的原代人和小鼠星形胶质细胞中。我们的初步数据还表明，HIV-1通过NF-：B依赖性途径间接诱导星形胶质细胞，该途径与白介素6（IL-6）的产生相关。基于以下发现，正常脑发育过程中的突触重塑需要C3，我们假设HIV感染期间大脑中的C3过表达会引发异位突触重塑和神经病发生。在此应用中，我们提出探索性研究，以在两个具体目的中检验这一假设：1。我们将通过完整的HIV-1和TAT确定星形胶质细胞中C3诱导的机理，重点是HIV-1诱导的IL-6作为中介体的潜在作用。 2。我们将确定一种与HIV-1相关的神经病发生的小鼠模型，最适合于HIV-1或TAT在大脑中对C3和IL-6诱导以及激活补体在突触中的沉积。拟议的探索性研究应建立概念基础和实验工具，以详细研究补体及其潜在诱导者HIV和IL-6在HIV介导的神经病发生中的作用。这些研究将包括培养原代星形胶质细胞中HIV和TAT的实验，并将评估三种现有的HIV神经病生成的小动物模型，包括将HIV-1感染的合成体星形胶质细胞移植到小鼠大脑中，这些星形胶质细胞向小鼠大脑的移植，表达了表达同型体形胶质细胞，从而直接通过Miice chimeric hiv进行了Mivereric HIV。每个系统将使用WildType，C3敲除和IL-6敲除小鼠。该项目涉及的研究学科包括逆转录病毒学，分子生物学，神经生物学，神经病理学和动物研究。该项目解决了与艾滋病毒相关的神经认知疾病的日益增长的公共卫生问题。如果成功的话，这项工作中特征的小动物模型可以用于对指定的治疗方法进行翻译研究，以应对大脑中补体和IL-6的潜在神经退行性作用。公共卫生相关性：HIV-1感染一直是全球大流行。得知美国新感染的发病率在美国估计，近年来纽约的速度实际上正在增加。因此，这种祸害仍然是一个严重的公共卫生挑战。该应用程序解决了一种在HIV-1感染者中持续存在的疾病，即神经认知障碍。神经系统功能障碍可能是由彻底的细胞死亡引起的，但最近的研究也表明神经元功能障碍在HIV-1感染大脑中的重要性。该应用的重点是通常发生在发育中的大脑中的突触消除机制，但在HIV-1感染过程中可能会颠覆。这种途径需要补体成分C3的表达，这是HIV-1感染期间大脑中升高的血清蛋白的表达，如下所示。提出的是对原发性星形胶质细胞过表达的机理的研究，这是大脑中最多的细胞。转向了解该过程在大脑中的影响，将研究三种HIV-1神经病发生的小鼠模型，以使C3表达和突触消除的显着性，这是神经变性的清晰途径。如果成功的话，这种发展应用将为应对HIV-1感染期间发生的神经元功能障碍的新的，生理上相关的途径提供重要的潜在客户。