Protein Misfolding Diseases and Oxido-Reductive Pathways

蛋白质错误折叠疾病和氧化还原途径

基本信息

批准号：
8143267
负责人：
Ivor James Benjamin
金额：
$ 74万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143267
关键词：
Award Cardiomyopathies Cells Cessation of life Clinical Couples Diagnostic Disease Drosophila genus Drosophila melanogaster Exhibits Functional disorder Genes Genetic Screening Glucosephosphate Dehydrogenase Goals Heart Heart Diseases Heart failure Human Hypertrophy Imaging Techniques Inherited Laboratories Life Monitor Mus NADP Neurodegenerative Disorders Oxidation-Reduction Oxidative Stress Pathway interactions Patients Reducing Agents Stress Study models System Therapeutic Thinking Tissues Toxic effect Validation Work abstracting biological adaptation to stress design effective therapy novel prevent protein folding protein misfolding research study therapeutic target tool

Award Cardiomyopathies Cells Cessation of life Clinical Couples Diagnostic Disease Drosophila genus Drosophila melanogaster Exhibits Functional disorder Genes Genetic Screening Glucosephosphate Dehydrogenase Goals Heart Heart Diseases Heart failure Human Hypertrophy Imaging Techniques Inherited Laboratories Life Monitor Mus NADP Neurodegenerative Disorders Oxidation-Reduction Oxidative Stress Pathway interactions Patients Reducing Agents Stress Study models System Therapeutic Thinking Tissues Toxic effect Validation Work abstracting biological adaptation to stress design effective therapy novel prevent protein folding protein misfolding research study therapeutic target tool

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项目摘要

DESCRIPTION Abstract Certain inherited modes of heart failure and several neurodegenerative diseases are characterized by protein misfolding states whose underlying mechanism(s) and pathophysiology are poorly understood. Effective therapies exist primarily as goals, not as clinical implementations. Macromolecular damage induced by oxidative stress is the sine qua non for thinking about many diseases. Our laboratory has challenged this paradigm by demonstrating that mouse hearts exhibiting protein-folding cardiomyopathy found in humans are under 'reductive stress' from an over-active antioxidative system. Decreasing the function of glucose-6-phosphate dehydrogenase (G6PD), which generates the reductant NADPH, "cures" the disease in mice by ameliorating reductive stress, aggresome formation, hypertrophy, heart failure and death. This experiment defines a novel causal mechanism and implicates G6PD as a potential therapeutic target. We hypothesize that stress response and anti-oxidative pathways undergo a pathogenic transition, and become dysregulated by macromolecular stresses (e.g., misfolded proteins). We further propose that other cardiac and neurodegenerative diseases result from similar pathogenic transition. Our Pioneer Award proposal is designed to develop a robust experimental platform for exploring the mechanisms of reductive stress disease. Our work will extend from studies that model reductive stress in the genetically amenable fruit fly Drosophila melanogaster, through cultured mouse and human cells, to whole mice, and finally into patients as we work to develop diagnostic tools. Cuttingedge imaging techniques will be developed for monitoring redox couples and toxicities in living cells and tissues. Genetic screens in Drosophila will guide the identification of new genes and determine the effects of potentially therapeutic compounds that prevent reductive stress disease. Validation in mice of interacting genes and pathways will provide us target candidates for pharmacolog

描述抽象的心力衰竭的某些遗传模式和几种神经退行性疾病的特征是蛋白质错误折叠状态，其基本机制和病理生理学的理解很少。有效的疗法主要是目标，而不是临床实施。氧化应激引起的大分子损伤是对许多疾病的思考的正弦物质。我们的实验室通过证明在人类中发现的蛋白质折叠心肌病的小鼠心脏在过度活跃的抗氧化系统中表现出蛋白质折叠的心肌病，从而挑战了这一范式。通过改善还原应力，肥大，心力衰竭，心力衰竭和死亡来降低产生还原剂NADPH的葡萄糖-6-磷酸脱氢酶（G6PD）的功能。该实验定义了一种新的因果机制，并将G6PD视为潜在的治疗靶点。我们假设应激反应和抗氧化途径会经历致病性转变，并因大分子应激（例如，错误折叠的蛋白质）的失调。我们进一步提出，其他心脏和神经退行性疾病是由类似的致病性转变引起的。我们的先锋奖提案旨在开发一个强大的实验平台，用于探索还原应力疾病的机制。我们的工作将从研究遗传性果蝇果蝇中的还原应力的研究扩展到，而在我们努力开发诊断工具的过程中，遗传性果蝇果蝇和人类细胞，全鼠培养的小鼠和人类细胞，最后是患者。将开发切切的成像技术来监测活细胞和组织中的氧化还原夫妇和毒性。果蝇中的遗传筛选将指导新基因的鉴定，并确定预防减少应激疾病的潜在治疗化合物的作用。相互作用基因和途径的小鼠验证将为我们提供药物的目标候选