Molecular Mechanisms in Trypanosoma cruzi Cardiomyopathy in AIDS

描述（由申请人提供）：恰加斯病是由原生动物寄生虫T。cruzi，现在被认为是一种新出现的艾滋病毒/艾滋病相关的机会性感染。免疫抑制后，休眠微生物重新激活，导致心肌炎和坏死性脑炎。由于接受HAART治疗的HIV感染患者可以存活多年，因此随着其免疫状态的变化，可能会出现反复的再激活。因此，进行性心肌炎和心血管重塑以及慢性心肌病可能会以更快的方式发展。在本申请中，我们将心室重塑定义为心肌损伤后结构和功能的变化以及特征性分子变化。这些变化是炎症和/或坏死的结果。T.心肌的克氏感染导致扩张型心肌病。我们的总体目标是研究一些重要的信号通路参与心脏重塑的结果，T。克氏感染我们计划研究T. Cruzi感染对细胞周期蛋白的影响。cruzi诱导的ERK激活调节细胞周期蛋白的表达和/或活性，细胞周期蛋白作为细胞增殖和分化的介质发挥作用。细胞周期蛋白负责心血管系统的重塑。因此，受感染的培养细胞和共培养系统中细胞周期蛋白表达的动力学。既然我们已经证明了T. cruzi诱导细胞周期蛋白D1的表达，我们将确定参与调节细胞周期蛋白D1启动子激活心脏成纤维细胞采用瞬时转染/启动子分析的分子机制。我们计划确定T.克氏杆菌感染对慢性肺心病小鼠模型细胞周期蛋白的影响。cruzi感染后，心肌细胞ERK、转录因子AP-1和NF-κ B激活，细胞周期蛋白D1表达增加。因此，在恰加斯病小鼠模型中，T.将确定Cruzi感染的小鼠并将其与心肌病的进展相关联。心肌中这些蛋白质改变的机制将通过多种技术包括免疫复合物测定和细胞增殖实验来研究。将利用小鼠模型研究细胞周期蛋白D1在心血管重构中的作用，所述小鼠模型包括细胞周期蛋白D1缺失小鼠和其中NF-γ.d3和ET-1已被选择性地从心肌细胞中删除的小鼠。这些研究将导致更好地了解心脏重塑的chagglutinocardiomyopathy，一个新兴的机会性感染艾滋病。此外，它还将为后续治疗提供潜在的靶点。

DESCRIPTION (provided by applicant): Chagas' disease is caused by the protozoan parasite T. cruzi and is now recognized as an emerging HIV/AIDS-related, opportunistic infection. Subsequent to immunosuppression there is reactivation of dormant organisms leading to myocarditis and necrotizing encephalitis. Since HIV-infected patients receiving HAART live for many years there is the likelihood that there will be repeated episodes of reactivation as their immune status waxes and wanes. Hence, progressive myocarditis and cardiovascular remodeling and chronic cardiomyopathy will likely develop in a more rapid fashion. In this application we have defined ventricular remodeling as changes in structure and function following myocardial damage together with characteristic molecular changes. These changes are the result of inflammation and/or necrosis. T. cruzi infection of the myocardium results in a dilated cardiomyopathy. Our overall objective is to examine some of the important signaling pathways involved in cardiac remodeling as a consequence of the T. cruzi infection. We plan to examine the consequences of T. cruzi-infection on cyclins in vitro, Our investigations clearly indicate that T. cruzi-induced ERK activation modulates the expression and/or activity of cyclins, which function as mediators of cellular proliferation and differentiation. Cyclins are responsible for remodeling in the cardiovascular system. Therefore, the kinetics of the expression of cyclins in infected cultured cells and co-culture systems. Since we have demonstrated that T. cruzi induces expression of cyclin D1, we will determine the molecular mechanisms involved in regulation of cyclin D 1 promoter activation in cardiac fibroblasts employing transient transfection/promoter assays. We plan to determine the consequence of T. cruzi infection on cyclins in mouse models of chagasic heart disease on. During acute T. cruzi infection there is activation of ERK, transcription factors AP-1 and NF-kB and increased expression of cyclin D 1 in the myocardium. Therefore, in the mouse model of Chagas' disease the kinetics of expression of cell cycle regulatory proteins in the cells of the myocardium of T. cruzi-infected mice will be determined and correlated with progression of cardiomyopathy. The mechanisms underlying the alterations in these proteins in the myocardium will be investigated by a variety of techniques including immune complex assays and cell proliferation experiments. The contribution of cyclin D 1 in cardiovascular remodeling will be investigated utilizing mouse models including cyclin D1 null mice and mice in which NF-r.d3 and ET-1 have been selectively deleted from cardiac myocytes. These studies will lead to a better understanding of cardiac remodeling in chagasic cardiomyopathy, an emerging opportunistic infection in AIDS. In addition, it will provide potential targets of adjunctive therapy.