Mitochondrial Biomarkers of Cardiomyopathy and Cure in Chagas Disease

心肌病的线粒体生物标志物和恰加斯病的治疗

基本信息

批准号：
8666721
负责人：
Nisha Jain Garg
金额：
$ 19.36万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666721
关键词：
Abbreviations Acute Myocarditis Adverse effects Alzheimer&apos s Disease Argentina Biogenesis Bioinformatics Biological Assay Biological Markers Biopsy Carbonyl Cyanide m-Chlorophenyl Hydrazone Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell Death Signaling Process Cell Membrane Permeability Cell Survival Cell membrane Cells Chagas Disease Chronic Chronic Disease Clinical Collaborations Complex Computer software Country Cytochromes b DNA DNA Damage DNA-Binding Proteins DNA-Directed DNA Polymerase Defect Development Diabetes Mellitus Dilated Cardiomyopathy Disease Disease Management Disease Progression Disease susceptibility Drug toxicity Environmental Pollutants Ethics Eukaryotic Cell Event Exhibits Fluorescein Fluorescence Gene Expression Gene Proteins Genetic Glyceraldehyde Health Heart Heart Diseases Heart failure Human Huntington Disease Hydrazones In Vitro Incubated Individual Infection Inflammatory Response Iodides Knowledge Laboratories Latin America Lead Left ventricular structure Ligands Lipids Medicine Methodology Methods Mitochondria Modeling Molecular Outcome Oxidative Phosphorylation Oxidoreductase Parkinson Disease Pathology Patients Peripheral Blood Mononuclear Cell Phagocytes Pharmaceutical Preparations Pharmacotherapy Physiological Physiology Play Process Proteins RNA Reactive Oxygen Species Research Personnel Resources Ribosomal Proteins Risk Role SOD2 gene Sampling Scanning Shapes Signal Transduction Stimulus Testing Therapeutic Time Tissues Toxic effect Toxicity Tests Treatment Efficacy Tropical Disease Trypanosoma cruzi Vesicle Wood material base beta Actin burden of illness clinical risk cost cytochrome c oxidase density design diacetyldichlorofluorescein drug efficacy factor A high throughput screening improved in vitro Assay in vivo innovation intercellular communication mesoxalonitrile mitochondrial dysfunction novel patient oriented prevent prognostic protein expression public health relevance receptor response screening tool transcription factor transcriptomics treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Chagasic cardiomyopathy (CCM) is caused by the protozoan Trypanosoma cruzi, and represents the third greatest tropical disease burden globally. There are an estimated >300,000 patients in the US and >10 million patients in endemic countries, and total annual cost of Chagas disease management is estimated at >8 billion US dollars. A common feature of chagasic and other cardiovascular diseases is the functional changes in mitochondria as an outcome of changes in expression of genes/proteins involved in maintaining the oxidative phosphorylation (OXPHOS) pathway and mitochondrial biogenesis. In this proposal, we will develop tools to capture the mitochondrial alterations as an indicator of cardiac disease susceptibility and efficacy (or toxicity) of a particular treatment in chagasic patients. For this, we will utilize microparticles (MPs) that are released as fragments from the plasma membrane of eukaryotic cells, and play selective roles in intercellular communication; and peripheral blood mononuclear cells (i.e. PBMCs) that carry the inherent genetic signature of the host, and reflect the in vivo state of the body. Using these easily available patient samples, we will test a novel hypothesis that MPs and PBMCs carry the specific signature of CCM progression and the treatment efficacy, and these signatures can be captured via changes in mitochondrial physiology and biogenesis in high-throughput in vitro screening assays. The major preliminary observations supporting our hypothesis include (1) DNA damage in cardiomyocytes and heart biopsies of chagasic patients is associated with compromised mitochondrial biogenesis and gene expression for OXPHOS pathway, (2) MPs from chagasic patients influenced the mitochondrial function and cell viability in in vitro assays, and (3) mitochondrial sensitivity to drugs is integrated within the context of whole cells. We will employ cutting edge experimental and high-throughput methodologies, established in the PI's laboratory, to determine (1) whether MPs carry the signature of in vivo changes in mt physiology and biogenesis and predict the molecular processes associated with CCM progression, and (2) whether mt-based high-throughput screening will capture the drugs' effects and will be useful in designing the patient-oriented treatment for CCM. The knowledge gained from the coordinated analysis and modeling of MP-induced mitochondrial responses in aim 1 and mitochondrial toxicity of drugs in aim 2 will lead to improved control and therapeutic treatment strategies for chagasic (and other cardiomyopathy) patients. Relevance and innovation: The innovation lies in the idea that our high-throughput approach will look at mitochondria at the DNA, RNA, protein and functional levels and develop a compendium of biomarkers valuable in personalized medicine, for first predicting the risk of cardiac disease progression, and then determining if a particular treatment will have adverse effects or be inefficacious for an individual. Importantly, the tools we will develop will be applicable to other chronic diseases where mitochondria plays a role (e.g., diabetes, Alzheimer, Parkinson, Huntington) and to testing the toxicity of environmental pollutants.

描述（由申请人提供）：恰加斯心肌病（CCM）是由原生动物克氏锥虫引起的，是全球第三大热带疾病负担。据估计，美国有超过 30 万患者，流行国家有超过 1,000 万患者，恰加斯病管理的年度总成本估计超过 80 亿美元。恰加斯病和其他心血管疾病的一个共同特征是线粒体功能变化，这是参与维持氧化磷酸化 (OXPHOS) 途径和线粒体生物发生的基因/蛋白质表达变化的结果。在本提案中，我们将开发工具来捕获线粒体改变，作为心脏病易感性和特定治疗的功效（或毒性）的指标。查加斯病患者。为此，我们将利用从真核细胞质膜上以碎片形式释放的微粒（MP），并在细胞间通讯中发挥选择性作用；外周血单核细胞（即PBMC）携带宿主固有的遗传特征，反映机体的体内状态。使用这些容易获得的患者样本，我们将测试一个新的假设，即 MP 和 PBMC 携带 CCM 进展和治疗效果的特定特征，并且这些特征可以通过高通量体外筛选测定中线粒体生理学和生物发生的变化来捕获。支持我们假设的主要初步观察结果包括（1）恰加斯病患者心肌细胞和心脏活检中的 DNA 损伤与线粒体生物合成和 OXPHOS 途径基因表达受损有关，（2）来自恰加斯病患者的 MP 影响了线粒体功能和细胞活力。体外测定， (3)线粒体对药物的敏感性整合在整个细胞的范围内。我们将采用 PI 实验室建立的尖端实验和高通量方法，以确定 (1) MP 是否携带 mt 生理学和生物发生的体内变化特征，并预测与 CCM 进展相关的分子过程，以及 (2) 是否基于 mt 的高通量筛选将捕获药物的作用，并将有助于设计以患者为导向的 CCM 治疗方法。从目标 1 中 MP 诱导的线粒体反应和目标 2 中药物线粒体毒性的协调分析和建模中获得的知识将改善恰加斯病（和其他心肌病）患者的控制和治疗策略。相关性和创新：创新在于我们的高通量方法将在 DNA、RNA、蛋白质和功能水平上观察线粒体，并开发出对个性化医疗有价值的生物标志物概要，用于首先预测心脏病进展的风险，然后确定特定治疗是否会对个体产生不良影响或无效。重要的是，我们将开发的工具将适用于线粒体发挥作用的其他慢性疾病（例如糖尿病、阿尔茨海默病、帕金森病、亨廷顿病）以及测试环境污染物的毒性。