Humanized mice for Neuro AIDS

神经艾滋病人源化小鼠

基本信息

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
项目类别：
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

项目摘要

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.

描述（由申请人提供）：HIV-1 对人类细胞的特异性阻止了大多数哺乳动物物种的病毒感染。这限制了小动物模型在 HIV-1 神经发病机制研究中的使用。使用人类异种移植物移植到啮齿动物体内的现有模型具有很大的局限性。我们假设移植了 -/- CD34+ 造血干细胞的 NOD/scid-?c-/- 小鼠将在大脑中植入人类巨噬细胞/小胶质细胞。这些人源化动物能够进行慢性 HIV-1 感染并产生人类适应性免疫反应。我们将研究小鼠大脑中人类细胞网络的建立、它们对 HIV-1 的易感性以及控制 HIV-1 复制（在外周淋巴组织和大脑中）的机制。我们还将探索神经元损伤的机制，并将其与人类 HIV-1 相关脑病理学中涉及的已知因素相关联。为了验证这个模型，我们将使用两种方法：消耗人类 CD8+ 细胞以减少对病毒复制的控制，以及通过人类 CD40L 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。它将成为当今最著名的小动物模型，用于在新型人类免疫系统环境中研究 HIV-1 发病机制、治疗方法和疫苗开发。 HIV-1 对人类细胞的特异性阻止了大多数哺乳动物物种的病毒感染，并限制了使用小动物模型来研究 HIV-1 神经发病机制。我们将研究移植人类CD34+造血干细胞的NOD/scid-?c-/-小鼠大脑中人类细胞网络的建立、它们对HIV-1的易感性、控制HIV的机制-1复制和神经元损伤。该模型最适合 NeuroAIDS 研究。