CARDIAC LESIONS IN HIV1 TRANSGENIC MICE

描述 （摘自申请人摘要）本研究的长期目标 建议是了解细胞和分子机制， 在HIV-1转基因小鼠中观察到的心脏病变， 最近建造的。在这些小鼠中，HIV-1基因产物得到表达 在人类HIV-1感染的靶细胞，即CD4 + T细胞中， 细胞和树突/巨噬细胞谱系的细胞。心脏病变 与HIV-1感染者中描述的相似。的 研究人员希望了解这些心脏病的发病机制， 病变，更具体地说，打算：1）确定HIV-1基因 通过构建HIV-1导致这种心脏表型的产物 突变体; 2）为了表征在突变体中基因表达模式的变化， 3）鉴定HIV-1转基因小鼠心脏中表达HIV-1的细胞 通过原位杂交和免疫细胞化学方法检测心肌组织中的 每种细胞类型（T淋巴细胞和淋巴细胞）的贡献 树突状细胞/巨噬细胞谱系）与心脏病变的发展; 5） 确定特异性宿主基因（IL-6，TNF，R，iNOS， ICE）防止心脏病变的出现; 6）确定 单核细胞/巨噬细胞衍生的细胞因子在使用共培养物的心脏毒性中的作用 正常的HIV-1转基因巨噬细胞和心肌细胞;和7） 确定心肌细胞的凋亡是否是一个主要特征， 在这些小鼠中观察到心肌病。(End摘要）

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)