Pathways of Neuronal Damage Involving Macrophage-Glia Interactions In Vivo

体内涉及巨噬细胞-神经胶质相互作用的神经元损伤途径

• 批准号: 6703046
• 负责人: Howard E Gendelman
• 金额: $ 21.49万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6703046
• 关键词: AIDS dementia complex; HIV infections; SCID mouse; astrocytes; cell cell interaction; disease /disorder model; glia; growth factor; human immunodeficiency virus 1; human tissue; immunocytochemistry; inflammation; macrophage; magnetic resonance imaging; neuropathology; neurotrophic factors; nuclear magnetic resonance spectroscopy; postmortem; proteomics

We propose that astrocyte dysfunction in HIV-1-associated dementia (HAD) occurs through its Interactions with infected brain mononuclear phagocytes (MP; perivascular and parenchymal macrophages and microglia). We will study how this occurs taking advantage of a newly developed proteomics and imaging facllity within our center. Magnetic resonance imaging (1HMRI), 1HMRS spectroscopy and single proton emission computed tomography will access cell movement and functlon in a rodent animal model of human HAD and HIV encephalitis (HIVE). The work will investigate how MP Infection and/or activation affects astrocyte neuroregulatory functions as well as explore primary infection of astrocytes de novo. It is proposed that secretion of MP pro-inflammatory factors (for example, tumor necrosis factor, quinolinlc acid and platelet activating factor) attenuates astrocyte signaling pathways leading to the down regulation of glial trophins including brain derived neurotrophic factor, glial derived neurotrophic factor, nerve growth factor, and/or transforming growth factor beta as well as attenuating glutamate transporter function, HIV-infected macrophages secretions (cellular or viral products) may also inclte the production of neurotoxins from astrocytes (for example, nitric oxide), glutamate, interleukin-1beta, MP-astrocyte interactions will be investigated for their abilities to affect autocrine and/or paracrine amplification of glial neurotoxins and chemotactic function. The relative role of virus and astrocyte secretory responses will be studied for its influence in the neuropathogenesis of HIV infection in a severe combined immunodeficient (SCID) mouse model of human disease. SCID mice will be injected intracerebrally with productively infected human astrocytes with vesicular stomatitis virus expressing HIV-1, with lymphotropic (LAI) or macrophage tropic (DVJ, ADA or JR-FL) viruses. The generation of cytotoxlc T lymphocytes from reconstituted HIVE mice will be used to eliminate infected macrophages from the brain and permit the assessment and evaluation of astrocyte repair processes. Lastly, a novel, state-of-art proteomics facility that includes on-line protein sequencing, will establish a comprehensive database of global changes of protein expression in human primary astrocytes as it relates to cell functlon. Altogether, these works will permit the determination of astrocyte and neuronal functions evaluated as a consequence of HIV-1 infection, MP function and chemotaxis in laboratory and animal models of human HAD. Most importantly, the project has strong collaborative ties with each of the other projects focusing on a unique but as yet understudied part of NeuroAIDS, namely the role played by astrocytes in the disease process.

我们提出，在HIV-1相关性痴呆（HAD）中，星形胶质细胞功能障碍通过其与受感染的脑单核吞噬细胞（MP;血管周围和实质巨噬细胞和小胶质细胞）的相互作用而发生。我们将研究这是如何发生的，利用我们中心新开发的蛋白质组学和成像设施。磁共振成像（1HMRI），1HMRS光谱和单质子发射计算机断层扫描将访问人类HAD和HIV脑炎（HIVE）的啮齿动物模型中的细胞运动和功能。这项工作将研究MP感染和/或激活如何影响星形胶质细胞的神经调节功能，以及探索星形胶质细胞的原发性感染。提示MP促炎因子的分泌（例如，肿瘤坏死因子、喹啉酸和血小板活化因子）减弱星形胶质细胞信号传导途径，导致神经胶质营养因子（包括脑源性神经营养因子、神经胶质源性神经营养因子、神经生长因子和/或转化生长因子β）的下调，以及减弱谷氨酸转运蛋白功能，HIV感染的巨噬细胞分泌物（细胞或病毒产物）也可能包括星形胶质细胞产生神经毒素（例如，一氧化氮）、谷氨酸、白细胞介素-1 β、MP-星形胶质细胞相互作用，将研究其影响神经胶质细胞神经毒素自分泌和/或旁分泌扩增和趋化功能的能力。将研究病毒和星形胶质细胞分泌反应的相对作用，以了解其对细胞增殖的影响。 在人类疾病的严重联合免疫缺陷（SCID）小鼠模型中HIV感染的神经发病机制。用表达HIV-1的水泡性口炎病毒、嗜淋巴细胞（LAI）或嗜巨噬细胞（DVJ、ADA或JR-FL）病毒对SCID小鼠进行脑内注射生产性感染的人星形胶质细胞。从重组HIVE小鼠中产生细胞毒性T淋巴细胞将用于从脑中清除感染的巨噬细胞，并允许评估和评价星形胶质细胞修复过程。最后，一个新的，最先进的蛋白质组学设施，包括在线蛋白质测序，将建立一个全面的数据库的全球变化的蛋白质表达在人类初级星形胶质细胞，因为它涉及到细胞functionlon。总之，这些工作将允许确定星形胶质细胞和神经元 作为HIV-1感染的结果，在实验室和人类HAD动物模型中评价MP功能和趋化性。最重要的是，该项目与其他每个项目都有很强的合作关系，这些项目专注于NeuroAIDS的一个独特但尚未充分研究的部分，即星形胶质细胞在疾病过程中发挥的作用。