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（由申请人提供）：由细胞内原生动物克氏锥虫引起的恰加斯心肌病 (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患恰加斯病的风险。我们证明，胆固醇升高会增加克氏锥虫的入侵速度，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低密度脂蛋白水平的显着增加有关。我们的研究表明：(i) 克氏锥虫在急性感染期间以脂肪组织 (AT) 为目标，脂肪组织是该寄生虫的能量来源和储存库，(ii) AT 急性感染导致脂肪酸显着减少和增加胆固醇，以及 重要的是，显着水平的脂肪分解（脂肪减少）和脂肪细胞坏死，（iii）在感染的急性阶段，脂肪分解导致血清脂质水平和寄生虫血症（血清寄生虫水平）增加，这两者在急性感染结束时均显着下降，（ iv) 到感染急性期结束时，心脏脂质水平和寄生虫负荷显着增加， (v) 心肌中 SREBP 表达和胆固醇水平升高与感染的不确定阶段相关， (vi) 慢性病期间心脏胆固醇水平仍然升高 (vii) ER 和线粒体氧化应激与急性感染相关，并在鼠恰加斯模型中持续至慢性阶段。在 CCM 患者中观察到脂肪营养不良和心脏胆固醇升高。这表明相互关联的 AT 心脏脂质代谢在 CCM 的发展中发挥着重要作用。然而，克氏锥虫在感染的不同阶段改变 AT 心脏脂质代谢的确切机制尚不清楚。基于这些观察，我们假设慢性 CCM 是通过脂质代谢的两种不同扰动而形成的； (1)急性感染诱导的脂肪分解和脂质流入心肌的增加，以及(2)不确定(中间)阶段感染相关的心肌中从头脂肪生成的诱导。简而言之，我们认为脂肪组织脂肪分解调节心脏脂质沉积，而心脏脂质稳态的改变导致 CCM。该提案的总体目标是研究克氏锥虫感染不同阶段的 CCM 进展过程中 AT 与心脏脂质代谢之间的机制联系。为了充分了解脂肪细胞和脂蛋白在人类 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方法来预防恰加斯心脏病的进展，目前尚无疫苗或有效药物可用。