Trypanosoma cruzi and AIDS: Role of the Adipocyte

描述（由申请方提供）：由原生动物寄生虫克氏锥虫引起的恰加斯病是拉丁美洲流行地区急性心肌炎和慢性心肌病的重要原因。近年来，它也被视为艾滋病毒/艾滋病患者的机会性感染。鉴于肥胖、糖尿病和艾滋病在发展中国家的增加，肥胖与传染病之间的关系已成为一个重要的问题。葡萄糖代谢的作用和脂肪细胞在急性和慢性恰加斯病发病机制中的作用从未得到充分探讨。初步数据表明T. Cruzi侵入培养的脂肪细胞，此外还侵入并存留在脂肪组织中，在那里它上调炎症介质。此外，这种寄生虫感染深刻地改变葡萄糖代谢和脂联素水平。在用这种寄生虫感染小鼠30天后，各种细胞因子和其他脂肪组织特异性蛋白质的表达发生变化。我们计划利用一种新的小鼠模型诱导脂肪萎缩，我们已经开发，以确定精确的时间参与的脂肪细胞在急性和慢性阶段的克氏锥虫感染。在这些小鼠中，我们将使用正葡萄糖钳夹程序表征代谢改变。脂肪细胞衍生因子脂联素广泛参与心脏病的发病机制，在HIV和急性克氏锥虫感染中均降低。使用脂联素缺失小鼠的新模型，将在克氏锥虫感染的小鼠中评价脂联素在心脏肥大中的作用。在这两种感染克氏锥虫的小鼠模型中，我们将通过免疫印迹分析、组织病理学和透射电子显微镜检查感染后15-300天不同时间点身体特定区域的脂肪。采用正常血糖胰岛素钳夹，将检查急性感染期间观察到的低血糖的根本原因，特别是肝脏葡萄糖代谢的调节。将确定急性和慢性高血糖对恰加斯病慢性期寄生虫再活化的影响。最后，我们将获得新的见解，在慢性阶段的克氏锥虫感染的脂肪因子脂联素的心脏保护作用。预计这些研究将有助于更好地了解Chagas病在代谢失调状态下的发展，如HIV脂肪营养不良患者，与胰岛素敏感性降低和脂联素循环水平降低相关。

DESCRIPTION (provided by applicant): Chagas' disease caused by the protozoan parasite Trypanosoma cruzi, is an important cause of acute myocarditis and chronic cardiomyopathy in endemic regions of Latin America. In recent years it has also seen observed as an opportunistic infection in individuals with HIV/AIDS. In view of the increase of obesity, diabetes and AIDS in developing world, the relationship between obesity and infectious diseases has become an important issue. The role of glucose metabolism and the role of the fat cell in the pathogenesis of both acute and chronic Chagas' disease have never been fully explored. Preliminary data indicates that T. cruzi invades cultured fat cells and in addition invades and persists in adipose tissue where it upregulates inflammatory mediators. Moreover, infection with this parasite profoundly alters glucose metabolism and adiponectin levels. Thirty days after infection of mice with this parasite, there are alterations in the expressions of various cytokines and other adipose tissue-specific proteins. We plan to utilize a novel mouse model of inducible lipoatrophy that we have developed to determine the precise temporal involvement of adipocytes during both the acute and the chronic stages of Trypanosoma cruzi infection. In these mice we will characterize the metabolic alterations using the euglycemic clamp procedure. The adipocyte-derived factor adiponectin has been widely implicated in the pathogenesis of heart disease and is reduced both in HIV and acute Trypanosoma cruzi infection. Using a novel model of adiponectin null mice, the role of adiponectin in cardiac hypertrophy will be evaluated in Trypanosoma cruzi infected mice. In both of these mouse models infected with Trypanosoma cruzi we will examine fat from specific regions of the body at various time points from 15-300 days post infection by immunoblot analysis, histopathology and transmission electron microscopy. Employing a euglycemic insulin clamp, the underlying causes for the hypoglycemia observed during acute infection, specifically the regulation of hepatic glucose metabolism, will be examined. The effects of acute and chronic hyperglycemia on the reactivation of parasites in the chronic phase of Chagas' disease will be determined. Finally, we will gain new insights into the cardioprotective role of the adipokine adiponectin during the chronic phase of Trypanosoma cruzi infection. It is expected that these studies will contribute significantly towards a better understanding of Chagas' disease development in dysregulated metabolic states such as HIV lipodystrophic patients, associated with decreased insulin sensitivity and decreased circulating levels of adiponectin.