Pathogenic contribution of lipid homeostasis to chagasic Cardiomyopathy

脂质稳态对恰加斯心肌病的致病作用

• 批准号: 9172479
• 负责人: Jyothi Falguni Nagajyothi
• 金额: --
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172479
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Affect; Apolipoproteins B; Area; Australia; Autopsy; Cardiac; Cardiac Myocytes; Cardiomyopathies; Case Study; Cells; Chagas Disease; Cholesterol; Cholesterol Homeostasis; Chronic; Country; Data; Developed Countries; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Dyslipidemias; Early Intervention; Economic Burden; Endoplasmic Reticulum; Epidemic; Epidemiology; Europe; Fat necrosis; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Frequencies; Functional disorder; Health; Healthcare Systems; Heart; Heart Diseases; Hepatocyte; Homeostasis; Human; Human Development; Immigrant; Immigration; Immunofluorescence Immunologic; Incubated; Infection; Inflammation; Intervention; Invaded; LDL Cholesterol Lipoproteins; Latin America; Lead; Link; Lipids; Lipolysis; Lipoproteins; Liver; Liver Dysfunction; Low Density Lipoprotein Receptor; Lysosomes; Mammalian Cell; Manuscripts; Metabolic; Metabolism; Mitochondria; Morbidity - disease rate; Mus; Myocardial dysfunction; Myocarditis; Myocardium; North America; Obesity; Organ; Parasites; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Play; Preparation; Publishing; Risk; Role; Sampling; Sarcomeres; Serum; Signal Pathway; Signal Transduction; South America; Staging; Stress; Survival Rate; Therapeutic Intervention; Tissues; Transgenic Mice; Transgenic Organisms; Transmission Electron Microscopy; Triglycerides; Trypanosoma cruzi; United States; Up-Regulation; Vaccines; adiponectin; apolipoprotein B-100; base; burden of illness; cholesterol biosynthesis; exhaust; fatty acid metabolism; glucose metabolism; heart function; in vivo; lipid biosynthesis; lipid metabolism; low density lipoprotein inhibitor; mortality; mouse model; neglected tropical diseases; novel; novel strategies; overexpression; parasite invasion; pathogen; prevent; western diet

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.

描述(由申请人提供)：由细胞内原生动物克氏锥虫引起的查加西克心肌病(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。全球化增加了北美、欧洲和澳大利亚等发达国家的恰加斯病风险。我们证明，升高的胆固醇增加了克氏毛滴虫的侵袭率，这种寄生虫利用低密度脂蛋白受体来入侵宿主细胞。寄生虫的入侵与心脏、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，在急性感染期间，溶酶体的pH和功能发生了变化。感染小鼠心脏脂肪酸(FA)和胆固醇代谢增加。透射电子显微镜显示感染小鼠心脏的线粒体、内质网和肌节发生变化。全身脂肪的动态平衡依赖于饮食、肝脏的脂肪生物合成和清除以及脂肪组织的脂肪分解和脂肪生成。我们已经证明，在急性感染期间，高脂饮食(HFD)小鼠的存活率更高，脂解率降低；然而，幸存的小鼠在感染的后期出现了心功能障碍，线粒体功能失调，脂质稳态改变和脂肪坏死。急性感染导致脂肪肝，增加胆固醇积聚和炎症。感染小鼠肝脏的胆固醇、甘油三酯、脂肪酸和葡萄糖代谢明显改变。我们的观察表明，克氏毛滴虫感染改变了全身和全身的脂平衡，使寄生虫在感染的不同阶段存活，并通过增加感染期间心肌中的脂肪生成和脂肪生成来调节心脏功能。基于这些观察，我们推测侵袭和急性感染过程中细胞内脂质水平的升高以及慢性感染过程中对胆固醇生物合成的需求可能会耗尽细胞内ER和线粒体的氧化能力，从而促进CCM的发展。此外，我们认为宿主脂质水平(饮食、血脂谱、脂质生物合成和肝脏和脂肪细胞的清除)与CCM的进展存在显著的相关性。为了充分认识脂平衡在人CCM发生发展中的作用，我们将利用新型转基因小鼠模型“huApo-B”和“FAT-ATTAC”来研究饮食/血脂/脂肪细胞与CCM的关系。了解慢性心绞痛的致病因素将有助于开发新的方法来预防萎缩性心脏病的进展。此外，该提案还将提供有关潜在相互作用的重要数据 在查加斯病流行地区，由于人口和流行病学向“西方饮食”的转变，肥胖、糖尿病和血脂异常的流行可能导致恰加斯病的病理生理学发生变化。