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: 7336348
• 负责人: HERBERT Bernard TANOWITZ
• 金额: $ 38.83万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336348
• 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(申请人提供)：恰加斯病是由原生动物寄生虫T.ruzi引起的，现在被认为是一种与艾滋病毒/艾滋病相关的新出现的机会性感染。在免疫抑制之后，休眠的生物体重新激活，导致心肌炎和坏死性脑炎。由于接受HAART治疗的艾滋病毒感染患者可以存活多年，随着其免疫状态的起伏，有可能会反复出现重新激活的情况。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。在这一应用中，我们将心室重构定义为心肌损伤后结构和功能的变化以及特征性的分子变化。这些变化是炎症和/或坏死的结果。克氏毛滴虫感染心肌会导致扩张型心肌病。我们的总体目标是研究一些重要的信号通路，这些信号通路参与了由于旋毛虫感染而导致的心脏重构。我们计划在体外研究克氏毛滴虫感染对细胞周期蛋白的影响，我们的研究清楚地表明，克氏毛虫诱导的ERK激活调节细胞周期蛋白的表达和/或活性，而细胞周期蛋白是细胞增殖和分化的中介。细胞周期蛋白负责心血管系统的重塑。因此，细胞周期蛋白在感染的培养细胞和共培养系统中的表达动力学。由于我们已经证明了克鲁兹毛滴虫诱导了细胞周期蛋白D1的表达，因此我们将通过瞬时转染/启动子分析来确定调控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。我们计划在查食性心脏病的小鼠模型中确定克氏毛滴虫感染对细胞周期蛋白的影响。在急性感染过程中，心肌中ERK、转录因子AP-1和NF-kB被激活，细胞周期蛋白D1表达增加。因此，在查加斯病小鼠模型中，细胞周期调节蛋白在感染弓形虫感染的小鼠心肌细胞中的表达动力学将被测定，并与心肌病的进展相关。心肌中这些蛋白质变化的潜在机制将通过各种技术来研究，包括免疫复合物分析和细胞增殖实验。将利用小鼠模型研究细胞周期蛋白D 1在心血管重构中的作用，包括细胞周期蛋白D 1缺失的小鼠和从心肌细胞中选择性地删除了核因子r.d3和ET-1的小鼠。这些研究将有助于更好地了解查格性心肌病的心脏重构，后者是艾滋病的一种新出现的机会性感染。此外，它还将为辅助治疗提供潜在的靶点。

项目成果

Bradykinin B2 Receptors of dendritic cells, acting as sensors of kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses.

• DOI: 10.1371/journal.ppat.0030185
• 发表时间: 2007-11
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Monteiro AC;Schmitz V;Morrot A;de Arruda LB;Nagajyothi F;Granato A;Pesquero JB;Müller-Esterl W;Tanowitz HB;Scharfstein J
• 通讯作者: Scharfstein J

Chagas' disease and AIDS.

• DOI: 10.1186/1475-9292-3-2
• 发表时间: 2004-05-13
• 期刊: Kinetoplastid biology and disease
• 作者: Vaidian, Anil K;Weiss, Louis M;Tanowitz, Herbert B
• 通讯作者: Tanowitz, Herbert B

Regulation of host cell cyclin D1 by Trypanosoma cruzi in myoblasts.

成肌细胞中克氏锥虫对宿主细胞周期蛋白 D1 的调节。

• DOI: 10.4161/cc.7.4.5327
• 发表时间: 2008
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Bouzahzah,Boumediene;Yurchenko,Vyacheslav;Nagajyothi,Fnu;Hulit,James;Sadofsky,Moshe;Braunstein,VickiL;Mukherjee,Shankar;Weiss,Hannah;Machado,FabianaS;Pestell,RichardG;Lisanti,MichaelP;Tanowitz,HerbertB;Albanese,Chris
• 通讯作者: Albanese,Chris