Role of Lipoproteins in Chagasic heart disease

脂蛋白在恰加斯心脏病中的作用

基本信息

批准号：
8385373
负责人：
Jyothi Falguni Nagajyothi
金额：
$ 25.05万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385373
关键词：
Acute Acute Myocarditis Adipose tissue Adopted Affect Affinity American Antilipemic Agents Apolipoprotein E Apolipoproteins B Area Arrhythmia Bile Acids Binding Binding Sites Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell Death Cells Central America Cessation of life Chagas Disease Cholesterol Chronic Cicatrix Coenzyme Q10 Communicable Diseases Country Data Developed Countries Developing Countries Development Diabetes Mellitus Diagnosis Diet Dietary intake Disease Progression Dyslipidemias Early treatment Enzymes Epidemic Europe Event Fatty acid glycerol esters Heart Heart Diseases Heart Hypertrophy Heart failure Hepatomegaly High Density Lipoproteins Histology Human Image Immigrant Immigration Immunofluorescence Immunologic In Vitro Infection Inflammation Intervention Invaded Investigation LDL Cholesterol Lipoproteins Laboratories Latin America Ligand Binding Lipids Lipolysis Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mammalian Cell Metabolic Methods Mitochondria Modality Mus Myocardial Myocarditis Myocardium Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids North America Obesity Organ Oxidative Stress Parasites Pathogenesis Patients Pharmaceutical Preparations Play Population Probucol Process Public Health Publishing Research Role Sampling Serum Signal Pathway Site South America Staging Staining method Stains Stroke Structure Thromboembolism Tissues Trypanosoma cruzi Very low density lipoprotein animal data atorvastatin base colesevelam economic implication heart cell improved inhibitor/antagonist microsomal triglyceride transfer protein migration mortality mouse model oil red O oxidation oxidized low density lipoprotein parasite invasion pathogen prevent social implication

项目摘要

DESCRIPTION (provided by applicant): Chagas disease, caused by an intracellular parasite Trypanosoma cruzi, is a major public health problem with significant social and economic implications in most Latin American countries and among immigrant populations in developing countries, and is responsible for millions of deaths annually. Chagasic heart disease is characterized by myocarditis associated with prominent fibrotic scarring, cardiac hypertrophy, arrhythmia, cardiomyopathy, heart failure and secondary thromboembolism. Mortality due to cardiovascular disease is increasing in the most developed countries of South and Central America with the change to a high fat "western" diet. 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 liver. Immunofluorescence analysis demonstrated an accumulation of LDL around parasites in the myocardium of infected mice. LDL, HDL and total cholesterol levels of hearts of infected mice were significantly increased compared to the hearts of uninfected mice. Acute infection caused myocarditis, hepatomegaly, lipolysis, impaired serum lipid levels, and elevated tissue/organ cholesterol. Serum lipoproteins such as LDL, very Low Density Lipoprotein (VLDL) and HDL likely play a major role in the progression of Chagasic heart disease as parasites have high affinity for lipoproteins and causes influx of these lipoproteins into cells during invasion. The accumulated lipoproteins may undergo oxidation and responsible for the development of lipotoxicity, oxidative stress, inflammation and cell death, and contribute to the development of cardiomyopathy during T. cruzi infection. This proposal explores the possible correlation between serum lipids, diet and the development of Chagasic heart disease which is a new area of investigation. Understanding the factors responsible for chronic Chagasic cardiomyopathy is critical in order to develop new methods to prevent the progression of Chagasic heart disease. This is especially important as the epidemic of obesity, diabetes and dyslipidemia in Chagas endemic regions has the potential for significant interactions with this pathogen, thus altering th normal pathogenic process. PUBLIC HEALTH RELEVANCE: Low Density Lipoprotein (LDL) and cholesterol play a major role in the progression of Chagasic heart disease. Chagasic heart disease is characterized by myocarditis associated with prominent fibrotic scarring, cardiac hypertrophy, arrhythmia, cardiomyopathy, heart failure and secondary thromboembolism, and is due to infection with Trypanosoma cruzi. It is a major public health problem with significant social and economic implications in Latin and South America as well as among immigrants to the USA. It is estimated to cause 50,000 deaths annually. With changes in the diet of developing countries in South and Central America there has been an epidemic of obesity, diabetes and dyslipidemia. T. cruzi utilizes LDL receptors for invasion and infection results in accumulation of LDL and cholesterol in cells/tissues, contributing to the pathogenesis of cardiomyopathy. The studies proposed in this application will significantly improve our understanding of the interaction between lipoproteins and this cardiomyopathy, which offers the best chance for early intervention strategies aimed at preventing this devastating heart disease.

描述（由申请人提供）：由克鲁兹的细胞内寄生虫锥虫引起的木马疾病是一个主要的公共卫生问题，在大多数拉丁美洲国家以及发展中国家的移民人群中，具有重大的社会和经济影响，并且每年造成数百万死亡。 chagasic心脏病的特征是心肌炎与明显的纤维化疤痕，心脏肥大，心律不齐，心肌病，心力衰竭和继发性血栓栓塞有关。在南美最发达国家，由于心血管疾病而导致的死亡率正在增加，随着脂肪“西方”饮食的变化。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肝脏等器官的LDL水平显着升高。免疫荧光分析表明，在感染小鼠的心肌中，寄生虫周围的LDL积累。与未感染小鼠的心脏相比，感染小鼠的LDL，HDL和总胆固醇水平显着增加。急性感染引起心肌炎，肝肿大，脂解，血清脂质水平受损以及升高的组织/器官胆固醇。血清脂蛋白，例如LDL，非常低的密度脂蛋白（VLDL）和HDL可能在chagasic心脏病的进展中起主要作用，因为寄生虫对脂蛋白具有高亲和力，并在入侵期间引起这些脂蛋白流入细胞中。累积的脂蛋白可能会经过氧化并负责脂肪毒性，氧化应激，炎症和细胞死亡的发展，并在克鲁齐（T. cruzi）感染期间有助于心肌病的发展。该建议探讨了血清脂质，饮食与chagasic心脏病的发展之间的可能相关性，这是一个新的研究领域。了解导致慢性cha性心肌病的因素对于开发新方法以防止chagasic心脏病的发展至关重要。这一点尤其重要，因为查加斯特有区域中肥胖，糖尿病和血脂异常的流行具有与这种病原体显着相互作用的潜力，从而改变了正常的致病过程。公共卫生相关性：低密度脂蛋白（LDL）和胆固醇在chagasic心脏病的进展中起主要作用。 chagasic心脏病的特征是与突出的纤维化疤痕，心脏肥大，心律不齐，心肌病，心力衰竭，心力衰竭和继发性血栓栓塞相关的心肌炎，并且是由于克鲁齐锥虫瘤而引起的。这是一个主要的公共卫生问题，在拉丁语和南美以及美国移民中具有重大的社会和经济影响。据估计，每年造成50,000人死亡。随着南美发展中国家饮食的变化，肥胖，糖尿病和血脂异常的流行病已经存在。 Cruzi利用LDL受体进行侵袭和感染导致细胞/组织中LDL和胆固醇的积累，从而导致心肌病的发病机理。本应用程序中提出的研究将大大提高我们对脂蛋白与这种心肌病之间相互作用的理解，该脂肪蛋白为防止这种毁灭性心脏病提供了早期干预策略的最佳机会。