Genetic analysis and regulation of amyloids flux in the Drosophila heart

果蝇心脏淀粉样蛋白通量的遗传分析和调控

• 批准号: 8244261
• 负责人: Girish C. Melkani
• 金额: $ 22.43万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244261
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Animal Model; Antioxidants; Architecture; Arctic Regions; Autophagocytosis; Biological; Biological Models; Cardiac; Cardiomyopathies; Cardiovascular system; Cell Death; Cells; Congenital Heart Defects; Defect; Dietary Supplementation; Disease; Disease model; Dorsal; Drosophila genus; Drosophila melanogaster; Early Diagnosis; Environment; Enzymes; Equilibrium; Event; Functional disorder; Geldanamycin; Gene Expression; Generations; Genetic; Genetic Models; Genetic Suppression; Genome; Goals; Heart; Heart Diseases; Heart failure; Human; Human Genome; Huntington Disease; Lead; Link; Modeling; Molecular Chaperones; Mutate; Mutation; Myocardium; Neurodegenerative Disorders; Neuropathy; Normal tissue morphology; Organism; Outcome Study; Oxidative Stress; Pathway interactions; Patients; Peptides; Performance; Physiological; Physiology; Prevalence; Production; Proteins; Quality Control; Reactive Oxygen Species; Regulation; Resveratrol; Risk Factors; Screening procedure; Stress; Superoxide Dismutase; System; Techniques; Testing; Time; Tissues; Toxic effect; Transgenic Organisms; Variant; comparative; fly; gene conservation; genetic analysis; human SOD2 protein; human disease; monorden; mutant; novel strategies; overexpression; polyglutamine; protein aggregation; protein folding; small molecule; therapy development; tripterine

DESCRIPTION (provided by applicant): Several human diseases are associated with the expression of mutated, misfolded and aggregation- prone amyloid proteins. Deposition of these amyloids, their proliferation or multimerization leads to the genesis of several neuropathies, including Alzheimer's and Huntington's diseases. Accumulation of amyloids in the human heart leads to cardiomyopathy. Despite several proteins being shown to be associated with cardiac amyloidosis, the precise mechanism that leads to the disease is poorly known. Recent evidence indicates that patients with Huntington's and Alzheimer's diseases demonstrate a greater occurrence of cardiovascular events but very little is known as to how these diseases lead to cardiac failure. Since many proteins are dependent on the cellular folding environment, we hypothesize that expression of HD- or AD-causing amyloids in the heart will disrupt the overall balance of protein folding quality control due to oxidative stress or global misfolding, resulting in loss of tissue function. To test our hypothesis, we will use the genetically tractable model organism Drosophila melanogaster and employ an integrative approach in exploration and suppression of cardiac amyloidosis. We propose to develop the first Drosophila model to investigate the cardiac defects associated with the accumulation of Alzheimer's and Huntington's disease-causing amyloid. Using the UAS-Gal4 expression system, we will express UAS-polyglutamine (for Huntington's) and UAS-A242 peptides (for Alzheimer's) in the Drosophila heart. We will examine the resulting cardiac defects at the physiological and cell biological levels. Furthermore, we will explore how expression of amyloid in the cardiac muscle afects expression of autophagy and other stress markers. We then plan to use genetic and pharmacological approaches to suppress cardiac amyloidosis. Genetic suppression of amyloids-induced cardiomyopathy will be attempted by over-expression of chaperones to reduce global protein unfolding or superoxide dismutase to ameliorate oxidative stress. We will also explore the effects of pharmacological agents such as chaperone inducers or antioxidants to ameliorate cardiac defects associated with amyloid accumulation. Our proposed study organism, Drosophila, with its high degree of gene conservation to the human genome and many techniques to manipulate its gene expression, will be an excellent model for exploring the mechanism of cardiac failure in Alzheimer's and Huntington's disease patients and may prove useful for developing therapies for human disease. Ultimately, once established, this model can be used for exploring genesis and suppression of cardiac amyloidosis linked with other amyloid precursor proteins. This proposal thus has broad applications and applies to cardiac, Alzheimer's and Huntington's diseases. All three diseases are devastating and the outcomes of this study may provide vital clues for their genesis. PUBLIC HEALTH RELEVANCE: Both Alzheimer's and Huntington's diseases are major risk factors for cardiac failure; the proposed study uses the model organism Drosophila melanogater for the first time to explore amyloid-induced cardiac dysfunction in these two major neurodegenerative diseases. We will use transgenic and pharmacological approaches for the suppression of the induced cardiac amyloidosis. This study is crucial for understanding the mechanism of cardiac failure in two major neuropathies and once established, this Drosophila model can be used to explore amyloid-induced cardiac failure associated with other amyloid precursor proteins.

描述（由申请人提供）：多种人类疾病与突变、错误折叠和易于聚集的淀粉样蛋白的表达相关。这些淀粉样蛋白的沉积、增殖或多聚化导致多种神经病的发生，包括阿尔茨海默病和亨廷顿病。人类心脏中淀粉样蛋白的积累会导致心肌病。尽管有几种蛋白质被证明与心脏淀粉样变性有关，但导致该疾病的确切机制却知之甚少。最近的证据表明，患有亨廷顿舞蹈症和阿尔茨海默病的患者心血管事件的发生率更高，但人们对这些疾病如何导致心力衰竭知之甚少。由于许多蛋白质依赖于细胞折叠环境，我们假设心脏中引起 HD 或 AD 的淀粉样蛋白的表达会由于氧化应激或整体错误折叠而破坏蛋白质折叠质量控制的整体平衡，从而导致组织功能丧失。为了检验我们的假设，我们将使用遗传易处理的模式生物果蝇，并采用综合方法来探索和抑制心脏淀粉样变性。我们建议开发第一个果蝇模型来研究与阿尔茨海默病和亨廷顿病引起的淀粉样蛋白积累相关的心脏缺陷。使用 UAS-Gal4 表达系统，我们将在果蝇心脏中表达 UAS-聚谷氨酰胺（用于亨廷顿舞蹈病）和 UAS-A242 肽（用于阿尔茨海默病）。我们将在生理和细胞生物学水平上检查由此产生的心脏缺陷。此外，我们将探讨心肌中淀粉样蛋白的表达如何影响自噬和其他应激标志物的表达。然后我们计划使用遗传和药理学方法来抑制心脏淀粉样变性。将通过过度表达分子伴侣以减少整体蛋白去折叠或超氧化物歧化酶以改善氧化应激来尝试对淀粉样蛋白诱导的心肌病进行基因抑制。我们还将探讨伴侣诱导剂或抗氧化剂等药物对改善与淀粉样蛋白积累相关的心脏缺陷的作用。 我们提出的研究生物体——果蝇，因其对人类基因组的高度保守性和许多操纵其基因表达的技术，将成为探索阿尔茨海默病和亨廷顿病患者心力衰竭机制的优秀模型，并可能对开发人类疾病的疗法有用。最终，一旦建立，该模型可用于探索与其他淀粉样前体蛋白相关的心脏淀粉样变性的发生和抑制。因此，该提议具有广泛的应用，适用于心脏病、阿尔茨海默病和亨廷顿病。这三种疾病都是毁灭性的，这项研究的结果可能为其起源提供重要线索。 公众健康相关性：阿尔茨海默病和亨廷顿病都是心力衰竭的主要危险因素；该研究首次使用模式生物果蝇来探索淀粉样蛋白诱导的这两种主要神经退行性疾病中的心脏功能障碍。我们将使用转基因和药理学方法来抑制诱导的心脏淀粉样变性。这项研究对于了解两种主要神经病的心力衰竭机制至关重要，一旦建立，该果蝇模型可用于探索与其他淀粉样蛋白前体蛋白相关的淀粉样蛋白诱导的心力衰竭。