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: 9127659
• 负责人: Jyothi Falguni Nagajyothi
• 金额: $ 24.35万
• 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/9127659
• 关键词: Pathogenic; contribution; lipid; homeostasis; chagasic

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（由申请方提供）：由细胞内原生动物克氏锥虫引起的恰格虫心肌病（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的南美锥虫病风险。我们证明，胆固醇升高会增加T。cruzi入侵，并且这种寄生虫利用LDLr入侵宿主细胞。寄生虫入侵与心脏和脂肪组织等器官中LDL水平的显著增加有关。我们的研究表明：（i）T. cruzi在急性感染期间靶向脂肪组织（AT），其充当该寄生虫的能量来源和储存库，（ii）在AT中，急性感染导致脂肪酸的显著减少和胆固醇的增加，以及 重要的是，脂肪分解水平显着（iii）脂肪分解导致血清脂质水平升高和寄生虫血症（iv）在急性感染期结束时，心脏脂质水平和寄生虫负荷显著增加，（v）心肌中SREBP和胆固醇水平的表达升高与感染的不确定阶段相关。 感染，和（vii）ER和线粒体氧化应激与急性感染相关，并在鼠恰加斯病模型中持续至慢性阶段。在CCM患者中观察到脂肪代谢障碍和心脏胆固醇升高。这表明，相互关联的AT-心脏脂质代谢在CCM的发展中起着重要作用。然而，T. cruzi在感染的不同阶段改变AT-心脏脂质代谢尚不清楚。基于这些观察结果，我们假设慢性CCM是通过两种不同的脂质代谢紊乱发展的;（1）急性感染诱导的脂解和脂质流入心肌的增加，和（2）不确定（中间）阶段感染相关的心肌新生脂肪生成诱导。总之，我们认为脂肪组织脂解调节心脏脂质沉积，改变心脏脂质稳态导致CCM。本研究的总体目标是探讨在T.克氏感染为了充分了解脂肪细胞和脂蛋白在人CCM发病机制中的作用，我们分别使用转基因“FAT-ATTAC”和双转基因“CETP-ApoB”小鼠。了解导致慢性CCM的因素将有助于开发新的方法来预防目前没有疫苗或有效药物的Chagglutinus心脏病的进展。