Protein Misfolding Diseases and Oxido-Reductive Pathways

描述 摘要 心力衰竭和一些神经退行性疾病的某些遗传模式以蛋白质错误折叠状态为特征，其潜在机制(S)和病理生理学尚不清楚。有效的治疗主要是作为目标而存在，而不是作为临床实施。氧化应激引起的大分子损伤是思考许多疾病的必要条件。我们的实验室对这一模式提出了挑战，证明了在人类中发现的蛋白质折叠心肌病的小鼠心脏处于过度活跃的抗氧化系统的“还原压力”之下。降低葡萄糖-6-磷酸脱氢酶(G6PD)的功能，产生还原剂NADPH，通过改善还原应激、侵袭体形成、肥大、心力衰竭和死亡来“治愈”小鼠的疾病。本实验确定了一种新的致病机制，并暗示G6PD是一个潜在的治疗靶点。我们假设，应激反应和抗氧化途径经历了致病的转变，并因大分子应激(例如，错误折叠的蛋白质)而变得失调。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转变引起的。我们的先锋奖提案旨在为探索减压性应激疾病的机制开发一个强大的实验平台。我们的工作将从对可遗传的果蝇黑腹果蝇建立减少压力模型的研究，通过培养小鼠和人类细胞，扩展到整个小鼠，最后在我们努力开发诊断工具的过程中扩展到患者。将开发尖端成像技术，用于监测活细胞和组织中的氧化还原对和毒性。果蝇的基因筛查将指导新基因的识别，并确定潜在的治疗化合物的效果，以预防减少性应激疾病。在小鼠身上验证相互作用的基因和途径将为我们提供药物学的目标候选

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