STUDIES OF LUNG DISEASES OF HIV TRANSGENIC MICE

HIV转基因小鼠肺部疾病的研究

• 批准号: 7645542
• 负责人: Paul Jolicoeur
• 金额: $ 28.16万
• 依托单位: CLINICAL RESEARCH INSTITUTE OF MONTREAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645542
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Alveolar; Alveolitis; Area; Atrophic; B-Cell Activation; Brain; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; CD8B1 gene; CXCR; CXCR4 Receptors; Cells; Central Nervous System Diseases; Chemokine (C-C Motif) Receptor 5; Child; Defect; Dementia; Dendritic Cells; Development; Diagnosis; Diffuse; Dilatation - action; Disease; Disease model; Follicular Dendritic Cells; Frequencies; Genes; Genetic; HIV Infections; HIV-1; Heart Diseases; Human; Hypergammaglobulinemia; Immune; Immune System Diseases; Immune system; Immunologic Deficiency Syndromes; Individual; Infection; Infiltration; Kidney Diseases; Langerhans cell; Lesion; Life; Lung; Lung diseases; Lymphocyte; Lymphoid; Lymphoid interstitial pneumonia; Maps; Mature T-Lymphocyte; Memory; Microglia; Modeling; Mouse Strains; Mucous Membrane; Mus; Opportunistic Infections; Organ; Pathogenesis; Pathology; Patients; Peripheral; Phenotype; Plasma Cells; Population; Predisposition; Proteins; Public Health; Pulmonary Hypertension; Research; Research Proposals; Sarcoidosis; Site; Spinal Cord Diseases; T-Lymphocyte; Tissues; Transgenic Mice; Tubular formation; Virus Receptors; base; cell type; chemokine; in vivo; interstitial; macrophage; monocyte; pathogen; receptor

DESCRIPTION (provided by applicant): The main objective of this research proposal is to understand the pathogenesis of some important pulmonary complications associated with HIV infection, using a murine model of these diseases, the CD4C/HIV Tg mice. These Tg mice express some of the gene products of HIV-1 in cells normally targeted by HIV-1 infection in humans, namely CD4+ CD8+ immature and CD4+ CD8- mature T cells and cells of the dendritic/macrophage lineage. The lung diseases observed in these Tg mice mimic the lung pathologies described in individuals with AIDS. Because these pathological lung lesions are associated with many other phenotypes very similar to those found in humans infected with HIV-1, we postulate that these Tg mice are relevant to human AIDS and that they constitute a very good model for the lung diseases associated with HIV-1 in humans. To understand the pathogenesis of this lung disease, we intend: AIM 1- To determine whether the development of the lung disease of CD4C/HIV Tg mice is caused by expression of HIV-1 Nef in cells of the immune system or in other cells. AIM 2- To identify the Nef-expressing cells required to induce lung disease in CD4C/HIV Tg mice. AIM 3- To determine, using an inducible trangene, whether the development of the lung disease in CD4C/HIV Tg mice occurs also when Nef is expressed later in life, in adulthood. AIIM 4- To map and identify the gene(s) responsible for the enhanced susceptibility of some strains of mice to the development of LIP in CD4C/HIV Tg mice. AIM 5- To determine whether there is a genetic basis for the development of sarcoidosis and pulmonary hypertension in CD4C/HIV Tg mice. This research is especially relevant to public health, especially children with AIDS, developing lung diseases at high frequency.

描述（由申请人提供）： 本研究计划的主要目的是使用这些疾病的小鼠模型（CD4C/HIV Tg 小鼠）了解与 HIV 感染相关的一些重要肺部并发症的发病机制。 这些 Tg 小鼠在人类 HIV-1 感染通常靶向的细胞中表达一些 HIV-1 基因产物，即 CD4+ CD8+ 未成熟 T 细胞和 CD4+ CD8- 成熟 T 细胞以及树突/巨噬细胞谱系的细胞。 在这些 Tg 小鼠中观察到的肺部疾病与艾滋病患者中描述的肺部病理相似。 由于这些病理性肺部病变与许多其他表型相关，这些表型与感染 HIV-1 的人类中发现的表型非常相似，因此我们推测这些 Tg 小鼠与人类艾滋病相关，并且它们构成了人类与 HIV-1 相关肺部疾病的非常好的模型。 为了了解这种肺部疾病的发病机制，我们打算： 目的 1-确定 CD4C/HIV Tg 小鼠肺部疾病的发生是否是由免疫系统细胞或其他细胞中 HIV-1 Nef 的表达引起的。 目标 2- 鉴定在 CD4C/HIV Tg 小鼠中诱导肺部疾病所需的 Nef 表达细胞。 目的 3-使用诱导转基因确定 CD4C/HIV Tg 小鼠中肺病的发展是否也会在 Nef 在生命后期（成年期）表达时发生。 AIIM 4 - 绘制和鉴定导致某些小鼠品系对 CD4C/HIV Tg 小鼠中 LIP 发展易感性增强的基因。 目标 5-确定 CD4C/HIV Tg 小鼠中结节病和肺动脉高压的发生是否存在遗传基础。 这项研究与公共卫生尤其相关，特别是患有艾滋病的儿童，他们经常患上肺部疾病。

项目成果

Selective expression of human immunodeficiency virus Nef in specific immune cell populations of transgenic mice is associated with distinct AIDS-like phenotypes.

人类免疫缺陷病毒 Nef 在转基因小鼠特定免疫细胞群中的选择性表达与独特的艾滋病样表型相关。

• DOI: 10.1128/jvi.00125-09
• 发表时间: 2009
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Hanna,Zaher;Priceputu,Elena;Chrobak,Pavel;Hu,Chunyan;Dugas,Véronique;Goupil,Mathieu;Marquis,Miriam;deRepentigny,Louis;Jolicoeur,Paul
• 通讯作者: Jolicoeur,Paul