Humanized mice for Neuro AIDS

神经艾滋病人源化小鼠

• 批准号: 7472578
• 负责人: LARISA Y POLUEKTOVA
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472578
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Blood; Blood - brain barrier anatomy; Brain; Brain Pathology; CCR5 gene; CD34 gene; CD40 Ligand; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Chimerism; Chronic; Dendritic Cells; Development; Disease; Elements; Engraftment; Enlargement of lymph nodes; Event; Functional disorder; Gene Proteins; HIV; HIV-1; Hematopoietic stem cells; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin M; Infection; Inflammatory; Injection of therapeutic agent; Liver; Lymphatic Diseases; Lymphocyte; Lymphoid Tissue; Mature B-Lymphocyte; Mediating; Microglia; Modeling; Morphology; Mus; Myelogenous; Neurons; Neuropathogenesis; Newborn Infant; Pathogenesis; Peripheral; Phenotype; Placement; Predisposition; Production; Research; Rodent; Rodent Model; Specificity; Study models; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Today; Transplantation; Tropism; Umbilical Cord Blood; Viral; Virus; Virus Diseases; Xenograft procedure; cell motility; cell type; fetal; graft vs host disease; graft vs host reaction; human disease; insight; lymph nodes; macrophage; migration; mouse model; neuromechanism; neurotoxic; neurotrophic factor; novel; protein expression; receptor; reconstitution; research study; response; therapeutic vaccine; vaccine development

DESCRIPTION (provided by applicant): The specificity of HIV-1 for human cells precludes virus infection in most mammalian species. This limits the use of small animal models for the studies of HIV-1 neuropathogenesis. Existing models that use human xenografts into rodents have significant limitations. We hypothesize that NOD/scid-?c-/- mice transplanted with -/- CD34+ hematopoietic stem cells will engraft human macrophages/microglia in the brain. These humanized animals are able to mount chronic HIV-1 infection and develop human adaptive immune responses. We will investigate the establishment of a human cell network in mouse brain, their susceptibility to HIV-1 and the mechanisms involved in the control of HIV-1 replication (both in the peripheral lymphoid tissues and in the brain). We will also explore the mechanisms of neuronal damage and correlate them with known factors involved in human HIV-1-associated brain pathology. To validate this model we will use two approaches: depletion of human CD8+ cells to diminish control of viral replication, and stimulation of anti-viral immunity by human CD40L. These experiments will explore the application of the model and unmask possible restrictions for its use. It will be the best known small animal model as of today, to study HIV-1 pathogenesis, therapeutics and vaccine development in a novel human immune system setting. The specificity of HIV-1 for human cells precludes virus infection in most mammalian species and limits the use of small animal models for the studies of HIV-1 neuropathogenesis. We will investigate the establishment of a human cell network in the brain of NOD/scid-?c-/- mice transplanted with human CD34+ hematopoietic stem -/- cells, their susceptibility to HIV-1, the mechanisms involved in the control of HIV-1 replication and neuronal damage. This model will be the best suited for NeuroAIDS research.

性状（由申请方提供）：HIV-1对人细胞的特异性排除了大多数哺乳动物物种中的病毒感染。这限制了小动物模型在HIV-1神经发病机制研究中的应用。将人类异种移植物用于啮齿动物的现有模型具有显著的局限性。我们假设NOD/scid-？移植有-/-CD 34+造血干细胞的c-/-小鼠将在脑中植入人巨噬细胞/小胶质细胞。这些人源化动物能够感染慢性HIV-1并产生人类适应性免疫反应。我们将研究小鼠脑中人类细胞网络的建立，它们对HIV-1的易感性以及参与控制HIV-1复制的机制（包括外周淋巴组织和大脑）。我们还将探索神经元损伤的机制，并将其与人类HIV-1相关脑病理学中已知的因素相关联。为了验证该模型，我们将使用两种方法：耗尽人CD 8+细胞以减少对病毒复制的控制，以及通过人CD 40 L刺激抗病毒免疫。这些实验将探索该模型的应用，并揭示其使用的可能限制。它将是迄今为止最著名的小动物模型，用于在新的人类免疫系统环境中研究HIV-1发病机制、治疗和疫苗开发。HIV-1对人类细胞的特异性排除了大多数哺乳动物物种中的病毒感染，并限制了用于HIV-1神经发病机制研究的小动物模型的使用。我们将调查建立一个人类细胞网络的大脑NOD/scid-？c-/-小鼠移植人CD 34+造血干/-细胞，其对HIV-1的易感性，参与控制HIV-1复制和神经元损伤的机制。这种模型将是最适合神经艾滋病研究。