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）：由克鲁兹的细胞内原生动物锥虫引起的chagasic心肌病（CCM）是拉丁美洲特有地区死亡率和发病率的主要原因，据估计患有1500万种感染了该疾病的携带者。在包括北美，欧洲和澳大利亚在内的发达国家，全球化增加了Chagas疾病的风险。我们证明升高的胆固醇会提高克鲁齐侵袭的速率，并且该寄生虫利用LDLR侵入宿主细胞。寄生虫侵袭与心脏和脂肪组织等器官中的LDL水平显着升高。我们的研究表明：（i）在急性感染过程中，克鲁兹（I）靶向脂肪组织（AT），该组织充当该寄生虫的能源和储层，（ii）AT急性感染会显着降低脂肪酸，胆固醇和胆固醇和胆固醇的增加和增加。 重要的是，在急性感染的急性阶段，脂解的显着水平（iii）脂解的血清脂质水平和寄生虫（血清寄生虫水平）在急性感染期间重新降低，这两种均显着降低，到急性感染的结束，（IV）均显着降低（iv），并且在急性阶段（iv）急性降低了（V）的急性（V），Cardient（IV）的急性（V）均显着降低（V）。心肌中的SREBPS和胆固醇水平与不确定的感染阶段相关，（VI）心脏胆固醇水平在慢性期间仍然升高 感染，（vii）ER和线粒体氧化应激与急性感染有关，并在鼠Chagas模型中持续到慢性阶段。 CCM患者观察到脂肪营养不良和心脏胆固醇升高。这表明相互链接的心脏脂质代谢在CCM的发展中起着重要作用。然而，尚不清楚在不同感染阶段改变t. cruzi改变心脏脂质代谢的确切机制。基于这些观察，我们假设通过脂质代谢中的两个不同的扰动开发了慢性CCM。 （1）急性感染引起的脂解和脂质流入心肌的增加，以及（2）不确定的（中间）阶段感染相关的脂肪诱导，与心肌中的Noke Lipogenogeny诱导。简而言之，我们提出脂肪组织脂解会调节心脏脂质沉积，而心脏脂质稳态的改变会导致CCM。该提案的总体目的是研究在克鲁兹感染的不同阶段，在CCM进展中AT和心脏脂质代谢之间的机械联系。为了充分理解脂肪细胞和脂蛋白在人CCM发病机理中的作用，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，以防止目前尚无疫苗或有效药物可用的chagasic心脏病的发展。