A Systems Biology Approach To Cardiomyopathy in the D. Melanogaster Model System

黑腹果蝇模型系统中心肌病的系统生物学方法

基本信息

批准号：
8241213
负责人：
D Brian Foster
金额：
$ 25.78万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2012-08-27 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241213
关键词：
ATP phosphohydrolase Accounting Acetylation Address Adenosine Monophosphate Affect Arrhythmia Benign Bioenergetics Bioinformatics Biological Biological Models Biological Process Cardiac Cardiac Myocytes Cardiomyopathies Cell physiology Cessation of life Complex Computer Simulation Coupling Development Dilated Cardiomyopathy Disease Management Drosophila Proteins Drosophila genus Drosophila melanogaster Drug Design Functional disorder Future Gene Chips Genetic Genetic Polymorphism Genetic Screening Goals Grant Heart Heart Diseases Homologous Gene Human Impairment Incidence Intervention Lead Lesion Mammals Maps Measures Metabolic Methods Microfilaments Mitochondria Modeling Molecular Molecular Profiling Mus Mutation Myosin Heavy Chains Organ Orthologous Gene Oxidation-Reduction Pathway Analysis Patients Peptides Performance Phenotype Phosphorylation Physiological Population Post-Translational Protein Processing Predisposition Process Production Protein Kinase Proteins Proteomics Reaction Relative (related person)Restrictive Cardiomyopathy Risk Management Role Signal Transduction Structure System Systems Biology Techniques Testing Tissues Translating Tube Ursidae Family drug development fly follow-up genetic manipulation human disease infancy innovation models and simulation multidisciplinary mutant network models new therapeutic target novel novel therapeutics overexpression protein expression research study shear stress stem sudden cardiac death tool

项目摘要

DESCRIPTION (provided by applicant): Cardiomyopathies that stem from sarcomeric and cytostructural mutations are characterized by adverse cardiac remodeling and predisposition to both arrhythmia and sudden cardiac death. The pathophysiology is complex, as are molecular mechanisms that underlie it. Tackling this complexity systematically demands the development of new tools and models. Here, we outline a multidisciplinary systems biology approach to the study of cardiomyopathy in a model system that leverages the power of rapid genetic manipulation, Drosophila melanogaster. Long valued as a model of cardiac development, application to the study of cardiac disease is its infancy. In a technical breakthrough study, we have succeeded in using proteomic techniques to compile a protein compendium of the Drosophila cardiac tube. Using bioinformatics, we show that it bears hallmarks of heart tissue at the level of cellular componentry, biological processes and molecular functions. We have therefore begun to assess cardiac remodeling in Drosophila models of restrictive and dilated cardiomyopathy arising from sarcomeric lesions using quantitative proteomic methods. This proposal outlines our systems biology approach, by which profiles of protein expression and post-translational modification are translated to testable hypotheses by the application of bioinformatic ontological and network analyses. The perturbation of protein networks will be cross-referenced with simulations from mathematical models of mammalian integrated excitation-contraction coupling and bioenergetics (ECME). Network/Model simulations will be followed up with physiological assessments of aberrant function (e.g. bioenergetics, Ca2+ handling). Preliminary analysis indicates the restrictive cardiomyopathy mutant Mhc5 shows substantial metabolic remodeling, suggesting a possible role for adenosine monophosphate activated protein kinase (AMPK). We outline new technical innovations that we are pursuing as part of the arsenal to measure Drosophila heart performance. The immediate 2-year goal of this exploratory/development grant is to identify a set of novel protein candidates or PTM signatures that lead to altered biological activity in Drosophila models of restrictive and dilated cardiomyopathy. In short, we outline a strategy to streamline the search for genetic suppressors of restrictive and dilated cardiomyopathy i.e. targets for future rapid targeted knockdown and overexpression. Human homologues of these novel modified drosophila proteins may represent novel targets for therapeutic drug design. PUBLIC HEALTH RELEVANCE: This proposal describes an multi-disciplinary systems biology approach to the study of cardiomyopathy using the cardiac tube of the fruit fly as a model system. Quantitative proteomics, network analysis, computational modeling and functional studies will yield a "molecular fingerprint" of enlarged and dilated fly hearts. The relative importance of the proteins that make up these signatures can be quickly assessed in this model system; human versions of fly proteins could well be targets for new drug development approaches to restrictive and dilated cardiomyopathy.

描述（由申请人提供）：源自肉类和细胞结构突变的心肌病的特征是心脏不良重塑和心律不齐和心脏突然死亡的倾向。病理生理学很复杂，其基础的分子机制也很复杂。解决这种复杂性系统需要开发新工具和模型。在这里，我们概述了一种多学科系统生物学方法，用于在一个模型系统中研究心肌病的研究，该模型系统利用快速遗传操纵的力量，果蝇果蝇。长期以来，作为心脏发展模型，对心脏疾病的研究的应用是其起步阶段。在一项技术突破研究中，我们成功地使用了蛋白质组学技术来编译果蝇心管的蛋白质汇编。使用生物信息学，我们表明它具有心脏组织的标志，在细胞成分，生物过程和分子功能的水平上。因此，我们已经开始评估使用定量蛋白质组学方法引起的肌肉症和扩张性心肌病的果蝇模型中的心脏重塑。该建议概述了我们的系统生物学方法，通过应用生物信息学本体论和网络分析，将蛋白质表达和翻译后修饰的概况转化为可检验的假设。蛋白质网络的扰动将与来自哺乳动物综合激发 - 收缩偶联和生物能学（ECME）的数学模型的模拟进行交叉引用。网络/模型仿真将通过异常功能的生理评估进行后续（例如生物能，CA2+处理）。初步分析表明，限制性心肌病变突变体MHC5显示出大量的代谢重塑，这表明腺苷一磷酸腺苷活化蛋白激酶（AMPK）可能起作用。我们概述了我们作为阿森纳的一部分来衡量果蝇心脏表现的新技术创新。该探索性/开发赠款的直接2年目标是确定一组新型蛋白质候选者或PTM特征，从而导致果蝇模型的生物学活性改变了限制性和扩张性心肌病模型。简而言之，我们概述了一种策略，旨在简化限制性和扩张性心肌病的遗传抑制器，即未来快速靶向靶向敲低和过表达的目标。这些新型改良的果蝇蛋白的人类同源物可能代表了治疗药物设计的新靶标。公共卫生相关性：该提案描述了一种使用果蝇作为模型系统的心肌管研究心肌病的多学科系统生物学方法。定量蛋白质组学，网络分析，计算建模和功能研究将产生扩大和扩张的苍蝇心脏的“分子指纹”。可以在此模型系统中快速评估构成这些特征的蛋白质的相对重要性；蝇蛋白的人类版本很可能是新药开发方法的限制性和扩张性心肌病的目标。