Molecular Mechanisms in Trypanosoma cruzi Cardiomyopathy in AIDS

艾滋病中克氏锥虫心肌病的分子机制

• 批准号: 7162921
• 负责人: HERBERT Bernard TANOWITZ
• 金额: $ 39.59万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162921
• 关键词: AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Acute; Antigen-Antibody Complex; Apoptosis; Biological Assay; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cell Cycle Proteins; Cell Proliferation; Cells; Chagas Disease; Characteristics; Chronic; Coculture Techniques; Cultured Cells; Cyclin D1; Cyclins; Development; Dilated Cardiomyopathy; Disease; Encephalitis; Endothelin-1; Event; Fibroblasts; Fibrosis; Heart Diseases; Heart Hypertrophy; Highly Active Antiretroviral Therapy; Hypertrophy; Immune; Immune response; Immunosuppression; In Vitro; Infection; Inflammation; Investigation; Kinetics; Knockout Mice; Lead; Life; Mediator of activation protein; Molecular; Mus; Myocardial; Myocardial dysfunction; Myocarditis; Myocardium; NF-kappa B; Necrosis; Nitric Oxide Synthase; Opportunistic Infections; Organism; Parasites; Pathogenesis; Pathologic; Pathway interactions; Patients; Proteins; Regulation; Regulatory Pathway; Role; Signal Pathway; Structure; System; Techniques; Therapeutic immunosuppression; Transcription Factor AP-1; Transfection; Trypanosoma cruzi; Ventricular Remodeling; Waxes; base; caveolin 1; genetic regulatory protein; mouse model; promoter; research study

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.

描述（由申请人提供）：恰加斯病是由原生动物寄生虫克氏锥虫引起的，现在被认为是一种新出现的与艾滋病毒/艾滋病相关的机会性感染。免疫抑制后，休眠生物体重新激活，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，因此随着他们的免疫状态的起伏，可能会出现反复的再激活。因此，进行性心肌炎、心血管重塑和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。心肌的克氏锥虫感染导致扩张型心肌病。我们的总体目标是检查克氏锥虫感染导致的心脏重塑中涉及的一些重要信号通路。我们计划在体外检查克氏锥虫感染对细胞周期蛋白的影响。我们的研究清楚地表明，克氏锥虫诱导的 ERK 激活调节细胞周期蛋白的表达和/或活性，而细胞周期蛋白充当细胞增殖和分化的介质。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。由于我们已经证明克氏锥虫诱导细胞周期蛋白 D1 的表达，因此我们将采用瞬时转染/启动子测定来确定参与调节心脏成纤维细胞中细胞周期蛋白 D 1 启动子激活的分子机制。我们计划在恰加斯心脏病小鼠模型中确定克氏锥虫感染对细胞周期蛋白的影响。在急性克氏锥虫感染期间，心肌中 ERK、转录因子 AP-1 和 NF-kB 被激活，细胞周期蛋白 D 1 的表达增加。因此，在恰加斯病小鼠模型中，将确定克氏锥虫感染小鼠心肌细胞中细胞周期调节蛋白的表达动力学，并将其与心肌病的进展相关联。将通过多种技术来研究心肌中这些蛋白质改变的机制，包括免疫复合物测定和细胞增殖实验。细胞周期蛋白 D 1 在心血管重塑中的作用将利用小鼠模型进行研究，包括细胞周期蛋白 D1 缺失小鼠和心肌细胞中选择性删除 NF-r.d3 和 ET-1 的小鼠。这些研究将有助于更好地了解恰加斯心肌病（艾滋病中一种新出现的机会性感染）的心脏重塑。此外，它将提供辅助治疗的潜在靶点。