UNDERSTANDING HEPATIC PROTEOSTASIS IN SYSTEMIC AMYLOID DISEASES

了解系统性淀粉样蛋白疾病中的肝脏蛋白质稳态

• 批准号: 10215499
• 负责人: GEORGE J MURPHY
• 金额: $ 62.23万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-14 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215499
• 关键词: ATF6 gene; Affect; Aging; Amyloid Fibrils; Amyloidosis; Biological; Cardiomyopathies; Cell Culture Techniques; Cells; Clinical; Deposition; Diagnosis; Disease; Disease model; Distal; Endoplasmic Reticulum; Genetic; Heart; Heart Diseases; Hepatic; Hepatocyte; Hepatotoxicity; Individual; Kidney; Kidney Diseases; Link; Liver; Liver diseases; Modeling; Molecular; Molecular Conformation; Mutation; Neuropathy; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Pharmacology; Physiological; Prealbumin; Prevalence; Protein Biosynthesis; Protein Secretion; Proteins; Proteomics; Publishing; Regulation; Role; Serum; Signal Pathway; Signal Transduction; Site; Stress; Structure; Therapeutic; Tissues; Toxic effect; Variant; arm; base; defined contribution; endoplasmic reticulum stress; extracellular; induced pluripotent stem cell; mouse model; non-Native; novel; novel therapeutics; proteostasis; response; transcription factor

PROJECT SUMMARY Systemic amyloid diseases are a class of disorders pathologically associated with the aggregation and deposition of destabilized, amyloidogenic proteins on peripheral target tissues distal from the site of protein synthesis such as the kidney, gut, heart, and peripheral nerves. Over 1 million individuals have been diagnosed with these deadly diseases, although this is likely a significant underestimate of disease prevalence as many undiagnosed renal and cardiac disorders are now being shown to involve systemic amyloid disease pathology. Destabilizing mutations in over 15 different proteins, the majority of which are synthesized in the liver, predispose individuals to systemic amyloid diseases. Since the pathology of these diseases is tightly linked to the site of deposition, systemic amyloid diseases have traditionally been viewed as disorders of the affected peripheral target tissues (e.g. renal disease, cardiomyopathy, and neuropathy). However, over the past 10 years, significant clinical and biological evidence has revealed a critical role for the liver in dictating the extracellular aggregation and deposition of amyloidogenic proteins. These results have challenged the traditional view of systemic amyloid diseases and indicate that these disorders may be best viewed as diseases of the liver. However, the mechanisms by which the liver contributes to systemic amyloid disease pathogenesis remain poorly defined. Here, we hypothesize that imbalances in liver endoplasmic reticulum (ER) protein homeostasis (or proteostasis) promotes the toxic extracellular aggregation of amyloidogenic proteins implicated in systemic amyloid disease pathogenesis. Significant published results from our groups strongly support a critical role for liver ER proteostasis in the toxic aggregation of liver-derived amyloidogenic proteins such as transthyretin (TTR). We showed that disrupting or enhancing ER proteostasis in cells secreting destabilized, amyloidogenic proteins such as TTR directly impacts their extracellular aggregation into toxic oligomers and amyloid fibrils implicated in systemic amyloid disease pathogenesis. Here, we will show that imbalances in liver ER proteostasis promotes the extracellular aggregation and peripheral toxicity of multiple amyloidogenic proteins. These results will demonstrate that diverse genetic, environmental, or aging-related factors that impact ER proteostasis in the liver can promote peripheral toxicity of multiple liver-synthesized amyloidogenic proteins, establishing a molecular framework to explain the clinical importance of the liver in the pathogenesis of these diseases. Furthermore, we will show that enhancing ER proteostasis in the liver through pharmacologic activation of endogenous unfolded protein response (UPR)-associated signaling pathways that regulate ER proteostasis offers a broadly-applicable strategy to ameliorate the secretion, extracellular aggregation, and peripheral toxicity of multiple amyloidogenic proteins. These results will establish pharmacologic UPR activation as a new therapeutic opportunity to treat this largely untreatable class of disease through a one drug:multiple disease therapeutic paradigm.

项目概要 系统性淀粉样蛋白疾病是一类病理上与淀粉样蛋白聚集和沉积相关的疾病。 不稳定的淀粉样蛋白沉积在远离蛋白质位点的外周靶组织上 肾脏、肠道、心脏和周围神经等合成。已有超过 100 万人被 被诊断患有这些致命疾病，尽管这可能大大低估了疾病的患病率 因为许多未确诊的肾脏和心脏疾病现在被证明与系统性淀粉样蛋白疾病有关 病理。超过 15 种不同蛋白质的不稳定突变，其中大部分是在 肝脏，使个体易患系统性淀粉样蛋白疾病。由于这些疾病的病理学是严格 与沉积位点相关，系统性淀粉样蛋白疾病传统上被视为 影响外周靶组织（例如肾病、心肌病和神经病）。然而，超过 过去 10 年来，重要的临床和生物学证据表明肝脏在决定机体健康方面发挥着关键作用。 淀粉样蛋白的细胞外聚集和沉积。这些结果挑战了 系统性淀粉样蛋白疾病的传统观点并表明这些疾病可能最好被视为 肝脏疾病。然而，肝脏导致系统性淀粉样蛋白疾病的机制 发病机制仍不明确。在这里，我们假设肝内质网（ER）失衡 蛋白质稳态（或蛋白质稳态）促进淀粉样蛋白的有毒细胞外聚集 参与系统性淀粉样蛋白疾病的发病机制。我们小组强烈发表的重要成果 支持肝脏 ER 蛋白稳态在肝源性淀粉样蛋白的毒性聚集中发挥关键作用 例如运甲状腺素蛋白（TTR）。我们发现，破坏或增强分泌细胞内质网的内质网蛋白稳态 不稳定的淀粉样蛋白（例如 TTR）直接影响其细胞外聚集成有毒物质 寡聚物和淀粉样原纤维参与系统性淀粉样蛋白疾病的发病机制。在这里，我们将展示 肝脏 ER 蛋白稳态失衡促进多种细胞外聚集和外周毒性 淀粉样蛋白。这些结果将证明，多种遗传、环境或衰老相关的因素 影响肝脏 ER 蛋白稳态的因素可促进多种肝合成的外周毒性 淀粉样蛋白，建立分子框架来解释肝脏在淀粉样蛋白中的临床重要性 这些疾病的发病机制。此外，我们将证明通过增强肝脏内质网蛋白稳态 内源性未折叠蛋白反应（UPR）相关信号通路的药理激活 调节 ER 蛋白质稳态提供了一种广泛适用的策略来改善分泌、细胞外 多种淀粉样蛋白的聚集和外周毒性。这些结果将建立 药理学 UPR 激活作为治疗这一类基本上无法治疗的疾病的新治疗机会 通过一种药物治疗疾病：多种疾病的治疗范例。