Pathogenic contribution of lipid homeostasis to chagasic Cardiomyopathy

描述（由申请人提供）：由细胞内原生动物克氏锥虫引起的恰加斯型心肌病（CCM）是拉丁美洲流行地区死亡和发病的主要原因，估计有1500万人感染或携带该疾病。全球化增加了包括北美、欧洲和澳大利亚在内的发达国家发生恰加斯病的风险。我们证明了升高的胆固醇增加了克氏锥虫的入侵率，这种寄生虫利用LDLr入侵宿主细胞。寄生虫入侵与心脏、肝脏和脂肪组织等器官中低密度脂蛋白水平的显著增加有关。免疫荧光分析显示急性感染期间溶酶体pH值和功能改变。感染小鼠心脏中脂肪酸（FA）和胆固醇代谢增加。透射电镜显示，感染小鼠心脏的线粒体、内质网和肌瘤发生了改变。全身脂质稳态依赖于饮食、肝脏脂质生物合成和清除以及脂肪组织的脂质分解和脂肪生成。我们已经证明，在急性感染期间，高脂肪饮食（HFD）小鼠的存活率更高，脂肪分解率降低；然而，存活的小鼠在感染和脂肪坏死的后期出现了线粒体功能障碍和脂质稳态改变的心功能障碍。急性感染引起脂肪肝，伴有胆固醇积累增加和炎症。感染小鼠肝脏中的胆固醇、甘油三酯、FA和葡萄糖代谢显著改变。我们的观察结果表明，克氏弓形虫感染在感染的不同阶段改变了寄生虫生存的全身和全身脂质稳态，并通过感染期间心肌脂肪生成和脂肪生成的增加来调节心脏功能。基于这些观察结果，我们假设侵袭和急性感染期间细胞内脂质水平升高，以及慢性感染期间胆固醇生物合成的需求可能耗尽细胞内内质网和线粒体氧化能力，从而促进CCM的发展。此外，我们认为宿主脂质水平（饮食、血清脂质谱、脂质生物合成和肝脏和脂肪细胞的清除）与CCM的进展存在显著相关性。为了充分了解脂质稳态在人类CCM发展中的作用，我们将使用新型转基因小鼠模型“huApo-B”和“FAT-ATTAC”来证明饮食/血清脂质/脂肪细胞与CCM之间的联系。了解导致慢性慢性心肌梗死的因素将有助于开发预防慢性心脏病进展的新方法。此外，该提案将提供潜在相互作用的重要数据

DESCRIPTION (provided by applicant): Chagasic Cardiomyopathy (CCM) caused by the intracellular protozoan Trypanosoma cruzi is a major cause of mortality and morbidity in the endemic regions of Latin America with an estimated 15 million infected with or are carriers of the disease. Globalization has increased the risk of Chagas disease in developed countries including North America, Europe and Australia. We demonstrated that elevated cholesterol increased the rate of T. cruzi invasion and that this parasite utilizes LDLr to invade host cells. Parasite invasion was associated with a significant increase in the levels of LDL in organs such as heart, liver and adipose tissue. Immunofluorescence analysis demonstrated altered lysosomal pH and function during acute infection. Increased fatty acid (FA) and cholesterol metabolism was observed in the hearts of infected mice. Transmission electron microscopy revealed altered mitochondria, ER and sarcomeres in the heart of infected mice. Whole body lipid homeostasis depends on diet, lipid biosynthesis and clearance of liver and lipolysis and adipogenesis of adipose tissue. We have documented there is a better survival rate for high fat diet (HFD) mice during acute infection with the reduced rate of lipolysis; however, the surviving mice developed cardiac dysfunction with dysfunctional mitochondria and altered lipid homeostasis at later stages of infection and fat necrosis. Acute infection caused fatty liver with increased cholesterol accumulation and inflammation. Cholesterol, triglyceride, FA and glucose metabolism are significantly altered in the liver of infected mice. Our observations suggest that T. cruzi infection alters systemic and whole body lipid homeostasis for parasite survival at different stages of infection and modulates the function of heart by increased adipogenesis and lipogenesis in the myocardium during infection. Based on these observations we hypothesize that the elevated intracellular lipid levels during invasion and acute infection, and the demand for cholesterol biosynthesis during chronic infection may exhaust intracellular ER and mitochondrial oxidative capacity and thus contribute to the development of CCM. Also, we believe a significant correlation between the host lipid levels (diet, serum lipid profile, lipid biosynthesis and clearance of liver and adipocyte) and the progression of CCM exist. In order to fully appreciate the role of lipid homeostasis in the development of human CCM, novel transgenic mice models " huApo-B" and "FAT-ATTAC" will be used to demonstrate the link between diet/serum lipids/adipocyte and CCM. Understanding the factors responsible for chronic CCM will aid in the development of new approaches to prevent progression of chagasic heart disease. In addition, this proposal will provide important data on the potential interactions of the epidemics of obesity, diabetes and dyslipidemia due to demographic and epidemiologic transition to a "western diet" in Chagas endemic regions that can result in changes in the pathophysiology of Chagas Disease.