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）：在各种神经退行性疾病中，补体成分在大脑中升高，但它们对神经发病机制的贡献尚不清楚。最近的研究表明，C1q和C3参与发育过程中的突触重塑，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相关痴呆期间，大脑中的C3升高a)；b)嵌合HIV-1感染小鼠；c)在培养中暴露于HIV-1的人和小鼠原代星形胶质细胞中。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中的C3，该途径与白细胞介素6 （IL-6）的产生相关。基于正常大脑发育过程中的突触重塑需要C3的发现，我们假设HIV感染期间大脑中C3的过表达引发了异位突触重塑和神经发病机制。在本申请中，我们提出探索性研究以验证这一假设，具体目的有两个：1。我们将确定完整的HIV-1和Tat诱导星形胶质细胞C3的机制，重点关注HIV-1诱导的IL-6作为中介的潜在作用。2. 我们将确定一种HIV-1相关神经发病机制的小鼠模型，该模型最适合研究大脑中HIV-1或Tat诱导C3和IL-6以及突触中活化补体的沉积。提出的探索性研究应该为详细研究补体及其潜在诱导剂HIV和IL-6在HIV介导的神经发病机制中的作用建立概念基础和实验工具。研究将包括在培养的原代星形胶质细胞中进行HIV和Tat的实验，并将评估现有的三种HIV神经发病的小动物模型，包括将HIV-1感染的同基因星形胶质细胞移植到小鼠脑中，将表达Tat的同基因星形胶质细胞移植到小鼠脑中，以及将嵌合HIV-1直接感染小鼠。每个系统将使用野生型、C3敲除和IL-6敲除小鼠。本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。该项目旨在解决与艾滋病毒相关的神经认知障碍这一日益严重的公共卫生问题。如果成功，本研究中的小动物模型可以用于针对补体和IL-6在大脑中潜在的神经退行性作用的治疗方法的转化研究。公共卫生相关性：艾滋病毒-1感染仍然是一种世界范围的大流行病。令人不安的是，在美国，新感染的发病率被低估了，而近年来纽约的发病率实际上正在上升。因此，这一祸害仍然是一项严重的公共卫生挑战。这个应用程序解决了hiv -1感染者中持续存在的一种疾病，神经认知障碍。神经系统功能障碍可由细胞完全死亡引起，但最近的研究也表明了HIV-1感染的大脑中神经元功能损伤的重要性。这种应用着重于突触消除机制，这种机制通常发生在发育中的大脑中，但在HIV-1感染期间可能被破坏。这一途径需要补体成分C3的表达，这是一种在HIV-1感染期间在大脑中发现的升高的血清蛋白，如图所示。建议对脑中数量最多的细胞——初代星形胶质细胞的过表达机制进行研究。为了了解这一过程在大脑中的影响，我们将研究三种HIV-1神经发病机制的小鼠模型，以了解C3表达和突触消除的显著性，这是神经退行性变的明确途径。如果成功，这一开发应用将为对抗HIV-1感染期间发生的神经元功能损伤的生理相关新途径提供重要线索。