CARDIAC LESIONS IN HIV1 TRANSGENIC MICE

描述 (摘自申请人的摘要)这项研究的长期目标 建议理解细胞和分子机制。 申请者在HIV-1转基因小鼠中观察到的心脏损害 最近建造的。在这些小鼠体内，HIV-1基因产物被表达 在人类感染HIV-1的细胞中，即CD4+T细胞中 树突状/巨噬细胞系的细胞和细胞。心脏损害 与HIV-1感染者身上描述的类似。这个 研究人员希望了解这些心脏疾病的发病机制。 损害，更具体地说，打算：1)鉴定HIV-1基因 通过构建HIV-1导致这种心脏表型的产品(S) 突变体；2)表征基因表达模式的变化 HIV-1转基因小鼠心脏；3)鉴定表达HIV-1的细胞 心脏原位杂交和免疫细胞化学；4)测定 每种细胞类型(T淋巴细胞和T细胞)的贡献 树突状细胞/巨噬细胞谱系)与心脏病变的发展有关；5) 确定特定宿主基因(IL-6、肿瘤坏死因子、受体、诱导型一氧化氮合酶、 ICE)预防心脏病变的出现；6)确定 单核/巨噬细胞衍生细胞因子在心脏毒性中的共培养 HIV-1转基因巨噬细胞和心肌细胞的正常；以及7)到 确定心肌细胞凋亡是否是心肌梗塞的主要特征 在这些小鼠身上观察到了心肌病。(摘要结束)

DESCRIPTION (Adapted from applicant's abstract) The long term objective of this research proposal is to understand the cellular and molecular mechanisms of the cardiac lesions observed in HIV-1 transgenic mice that the applicants have recently constructed. In these mice, the HIV-1 gene products are expressed in cells which are the target of HIV-1 infection in humans, namely CD4+T cells and cells of the dendritic/macrophage lineage. The cardiac lesions are similar to those described in HIV-1-infected individuals. The investigators would like to understand the pathogenesis of these cardiac lesions and more specifically, intend; 1) To identify the HIV-1 gene product(s) responsible for this cardiac phenotype by constructing HIV-1 mutants; 2) To characterize changes in the pattern of gene expression in the heart of HIV-1 transgenic mice; 3) To identify the cells expression HIV-1 in the heart by in situ hybridization and immunocyto-chemistry; 4) To determine the contributions of each cell type (T lymphocytes and cells of the dendritic/macrophage lineage) to the development of cardiac lesions; 5) To determine whether the ablation of specific host genes (IL-6,TNF,R, iNOS, ICE) prevents the appearance of cardiac lesions; 6) To determine the role of monocytes/macrophages derived cytokines in cardiotoxicity using cocultures of normal of HIV-1 transgenic macrophages and cardiomyocytes; and 7) To determine whether apoptosis of cardiomyocytes is a major feature of cardiomyopathy observed in these mice. (End of Abstract)