STUDIES OF LUNG DISEASES OF HIV TRANSGENIC MICE

描述(由申请人提供)： 这项研究计划的主要目的是利用这些疾病的小鼠模型CD4C/HIV TG小鼠来了解与HIV感染相关的一些重要肺部并发症的发病机制。这些转基因小鼠在人类通常以HIV-1感染为靶点的细胞中表达HIV-1的一些基因产物，即CD4+CD8+未成熟和CD4+CD8-成熟T细胞和树突状/巨噬细胞系细胞。在这些转基因小鼠身上观察到的肺部疾病与艾滋病患者所描述的肺部病理相似。由于这些病理肺损伤与许多其他表型与感染HIV-1的人类非常相似，我们推测这些TG小鼠与人类艾滋病有关，它们构成了与人类HIV-1相关的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转基因小鼠肺部疾病的发生是由HIV-1Nef在免疫系统细胞还是在其他细胞中的表达引起的。 目的2-鉴定在CD4C/HIVTG小鼠中诱导肺部疾病所需的Nef表达细胞。 目的3-利用一种可诱导的Trangene，确定在CD4C/HIV转基因小鼠中，当Nef在成年后表达时，是否也会发生肺部疾病的发展。 AIIM 4-定位和鉴定导致某些品系小鼠对CD4C/HIVTg小鼠LIP易感性增强的基因(S)。 目的5-确定CD4C/HIV转基因小鼠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特别相关，特别是患有艾滋病的儿童患肺部疾病的频率很高。

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.