STUDIES OF LUNG DISEASES OF HIV TRANSGENIC MICE

HIV转基因小鼠肺部疾病的研究

• 批准号: 7036392
• 负责人: Paul Jolicoeur
• 金额: $ 27万
• 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/7036392
• 关键词: AIDS; B lymphocyte; HIV infections; T lymphocyte; biotechnology; dendritic cells; developmental genetics; disease /disorder model; gene expression; genetic mapping; genetic markers; genetic susceptibility; genetically modified animals; hematopoietic stem cells; human immunodeficiency virus 1; laboratory mouse; lung disorder; macrophage; medical complication; microorganism immunology; pulmonary fibrosis /granuloma; pulmonary hypertension; regulatory gene; respiratory epithelium; sarcoidosis

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）： 本研究的主要目的是了解一些重要的肺部并发症与HIV感染的发病机制，使用这些疾病的小鼠模型，CD 4C/HIV Tg小鼠。 这些Tg小鼠在人类HIV-1感染通常靶向的细胞中表达HIV-1的一些基因产物，即CD 4 + CD 8+未成熟和CD 4 + CD 8-成熟T细胞和树突状/巨噬细胞谱系的细胞。 在这些Tg小鼠中观察到的肺部疾病模拟了患有AIDS的个体中描述的肺部病理。 由于这些病理性肺部病变与许多其他表型非常相似，发现在人类感染HIV-1，我们假设，这些Tg小鼠与人类艾滋病，他们构成了一个非常好的模型与人类HIV-1相关的肺部疾病。 为了了解这种肺部疾病的发病机制，我们打算： 目的1-确定CD 4C/HIV Tg小鼠肺部疾病的发展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。 目的2-鉴定诱导CD 4C/HIV Tg小鼠肺部疾病所需的Nef表达细胞。 AIM 3- 为了确定，使用可诱导的转基因，是否在CD 4C/HIV Tg小鼠的肺部疾病的发展也发生时，Nef表达在以后的生活中，在成年。 AIIM 4-绘制并鉴定导致某些品系小鼠对CD 4C/HIV Tg小鼠中LIP发展易感性增强的基因。 目的5-确定是否有一个遗传基础的发展结节病和肺动脉高压的CD 4C/HIV转基因小鼠。 这项研究与公共卫生特别相关，特别是患有艾滋病的儿童，他们经常患上肺部疾病。