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: 9188826
• 负责人: Jyothi Falguni Nagajyothi
• 金额: $ 41.42万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188826
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Affect; Affinity; Apolipoproteins B; Apoptosis; Area; Australia; Biogenesis; CETP gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Case Study; Cell Death; Cells; Chagas Disease; Cholesterol; Chronic; Country; Data; Deposition; Developed Countries; Development; Diabetes Mellitus; Disease; Early Intervention; Economic Burden; Energy-Generating Resources; Europe; Fatty Acids; Fatty acid glycerol esters; Frequencies; Genetic Transcription; Goals; Health; Healthcare Systems; Heart; Heart Diseases; Homeostasis; Human; Immigrant; Immigration; Infection; Intervention; Invaded; LDL Cholesterol Lipoproteins; Latin America; Lead; Link; Lipids; Lipodystrophy; Lipolysis; Lipoproteins; Low Density Lipoprotein Receptor; Mammalian Cell; Mediating; Metabolic; Mitochondria; Modeling; Morbidity - disease rate; Mus; Myocarditis; Myocardium; Necrosis; North America; Obesity; Organ; Outcome; Oxidative Stress; Parasitemia; Parasites; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phase; Physiology; Play; Research; Risk; Role; Serum; South America; Staging; Stress; Tissues; Transgenic Organisms; Trypanosoma cruzi; United States; Vaccines; World Health Organization; base; chagasic cardiomyopathy; lipid biosynthesis; lipid metabolism; low density lipoprotein inhibitor; mitochondrial dysfunction; mortality; mouse model; neglected tropical diseases; novel strategies; parasite invasion; pathogen; prevent

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 and adipose tissue. Our studies reveal that : (i) T. cruzi targets adipose tissue (AT) during acute infection which acts as an energy source and reservoir for this parasite, (ii) In AT acute infection results in a significant decrease in fatty acid and an increase in cholesterol, and importantly a significant level of lipolysis (fat loss) and fat cell necrosis, (iii) Lipolysis resuts in increased serum lipid levels and parasitemia (serum parasite level) during acute stage of infection both of which significantly decrease by the end of acute infection, (iv) By the end of acute stage of infection, cardiac lipid levels and parasite load are significantly increased, (v) Elevated expression of SREBPs and cholesterol levels in the myocardium associate with the indeterminate stage of infection, (vi) Cardiac cholesterol levels are still elevated during chronic infection, and (vii) ER and mitochondrial oxidative stress is associated with acute infection and persists to chronic stage in murine chagas model. Lipodystrophy and elevated cardiac cholesterol is observed in CCM patients. This suggests that interlinked AT-cardiac lipid metabolism play a major role in the development of CCM. However, the exact mechanisms through which T. cruzi alter AT-cardiac lipid metabolism at different stages of infection is not known. Based on these observations we hypothesize that chronic CCM is developed through two distinct perturbations in lipid metabolism; (1) acute infection-induced increase in lipolysis and lipid influx to myocardium, and (2) Indeterminate (intermediate) stage infection-associated induction of de novo lipogenesis in myocardium. In short, we propose that adipose tissue lipolysis regulates cardiac lipid deposition, and the altered cardiac lipid homeostasis results in CCM. The overall goal of this proposal is to investigate the mechanistic link between AT and cardiac lipid metabolism in the progression of CCM during different stages of T. cruzi infection. In order to fully appreciate the role of adipocytes and Lipoproteins in the pathogenesis of human CCM we are using transgenic "FAT-ATTAC" and double transgenic "CETP-ApoB" mice respectively. Understanding the factors responsible for chronic CCM will aid in the development of new approaches to prevent progression of Chagasic heart disease for which currently no vaccine or effective drug available.

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。寄生虫入侵与心脏和脂肪组织等器官中低密度脂蛋白水平的显著增加有关。我们的研究表明：(1)克氏锥虫在急性感染期间以脂肪组织（AT）为目标，AT是这种寄生虫的能量来源和储存库；(2)AT急性感染导致脂肪酸显著减少和胆固醇升高