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

基本信息

批准号：
7557119
负责人：
Howard E Gendelman
金额：
$ 22.16万
依托单位：
ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7557119
关键词：
AIDS Dementia Complex AIDS neuropathy Acids Adoptive Transfer Affect Amino Acid Sequence Amino Acid Transporter Animal Model Animals Antibodies Arts Astrocytes Attenuated Biochemical Biological Assay Biological Testing Blood Cells Brain Brain region Brain-Derived Neurotrophic Factor Cell Communication Cell Surface Proteins Cell secretion Cells Chemotaxis Choline Collaborations Complement Conditioned Culture Media Consequences of HIV Constitution Creatine Cytotoxic T-Lymphocytes Data Databases Disease Down-Regulation Emission-Computed Tomography Epidermal Growth Factor Evaluation Excision Excitatory Amino Acids Functional disorder Generations Genes Glial Fibrillary Acidic Protein Global Change Glutamate Transporter Glutamates HIV HIV Infections HIV encephalitis HIV-1 Histology Homeostasis Human Image Immune Immune response Immunity Indium Infection Infiltration Inflammatory Injection of therapeutic agent Interleukin-1 beta Interleukin-16 Interleukin-6 Interleukins Label Laboratories Laboratory Animal Models Lead Life Link Macrophage Chemotactic Factors Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Measures Membrane Microglia Molecular Monitor Mononuclear Mus N-acetylaspartate Nature Nerve Degeneration Nerve Growth Factors Neuroglia Neuronal Dysfunction Neurons Neuropathogenesis Neurophysiology - biologic function Neurotoxins Nitric Oxide Numbers PLAB Protein Pathway interactions Peptide Sequence Determination Phagocytes Platelet Activating Factor Process Production Proteins Proteomics Protons Radiolabeled Relative (related person)Rodent Role Role playing therapy SCID Mice Signal Pathway Spectrum Analysis Stimulus Structure System T-Lymphocyte TNF gene Test Result Testing Time Transforming Growth Factor beta Tumor Necrosis Factor-alpha Tumor Necrosis Factors Up-Regulation Vesicular stomatitis Indiana virus Viral Virus Virus Diseases Work autocrine brain tissue cell motility cell type comparative cytokine day human TNF protein human disease immunodeficient mouse model in vivo iron oxide macrophage magnetic resonance spectroscopic imaging migration molecular imaging monocyte mouse model neuroinflammation neurotoxic neurotrophic factor novel paracrine protein expression radiotracer reconstitution relating to nervous system repaired research study response subtraction hybridization tool

项目摘要

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.

我们认为，HIV-1 相关痴呆 (HAD) 中的星形胶质细胞功能障碍是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）的相互作用而发生的。我们将利用我们中心新开发的蛋白质组学和成像设备来研究这是如何发生的。磁共振成像 (1HMRI)、1HMRS 光谱和单质子发射计算机断层扫描将了解人类 HAD 和 HIV 脑炎 (HIVE) 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，并从头探索星形胶质细胞的原发感染。有人提出，MP促炎因子（例如肿瘤坏死因子、喹啉酸和血小板活化因子）的分泌减弱了星形胶质细胞信号通路，导致神经胶质细胞营养蛋白的下调，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）也可能包括将研究星形胶质细胞产生的神经毒素（例如一氧化氮）、谷氨酸、白细胞介素-1β、MP-星形胶质细胞相互作用，以了解它们影响神经胶质神经毒素的自分泌和/或旁分泌放大和趋化功能的能力。将研究病毒和星形胶质细胞分泌反应的相对作用，以了解其对人类疾病严重联合免疫缺陷（SCID）小鼠模型中 HIV 感染的神经发病机制。 SCID小鼠将被脑内注射有效感染的人星形胶质细胞，该星形胶质细胞带有表达HIV-1的水疱性口炎病毒、嗜淋巴细胞病毒（LAI）或嗜巨噬细胞病毒（DVJ、ADA或JR-FL）。来自重组 HIVE 小鼠的细胞毒性 T 淋巴细胞的产生将用于消除大脑中受感染的巨噬细胞，并允许评估和评估星形胶质细胞修复过程。最后，一个新颖、最先进的蛋白质组学设施，包括在线蛋白质测序，将建立一个与细胞功能相关的人类原代星形胶质细胞蛋白质表达全局变化的综合数据库。总而言之，这些工作将允许确定星形胶质细胞和神经元在人类 HAD 的实验室和动物模型中评估了 HIV-1 感染、MP 功能和趋化性的结果。最重要的是，该项目与其他每个项目都有很强的合作关系，重点关注神经艾滋病的一个独特但尚未得到充分研究的部分，即星形胶质细胞在疾病过程中所发挥的作用。