UNDERSTANDING HEPATIC PROTEOSTASIS IN SYSTEMIC AMYLOID DISEASES

项目总结 系统性淀粉样变性疾病是一类病理上与聚集和 失稳的淀粉样蛋白在蛋白质部位远端周围靶组织的沉积 如肾、肠、心脏和周围神经的合成。已经有100多万人被 被诊断出患有这些致命的疾病，尽管这很可能是对疾病流行率的严重低估 由于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 病理学。超过15种不同蛋白质的不稳定突变，其中大部分是在 肝脏易患全身性淀粉样变性疾病。因为这些疾病的病理机制 系统性淀粉样蛋白疾病与沉积部位有关，传统上被视为 受影响的外周目标组织(例如肾脏疾病、心肌病和神经病)。然而，在过去的几年里， 在过去的10年里，重要的临床和生物学证据表明，肝脏在决定 淀粉样蛋白的胞外聚集和沉积。这些结果挑战了 对全身性淀粉样变性疾病的传统观点，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，我们假设肝脏内质网(ER)的失衡。 蛋白质稳态(或蛋白质稳态)促进淀粉样蛋白的毒性胞外聚集 与全身性淀粉样变性疾病的发病机制有关。我们的团队发表了重要的研究成果 支持肝脏ER蛋白稳定在肝源性淀粉样变蛋白毒性聚集中的关键作用 如促甲状腺激素(TTR)。我们发现，扰乱或增强细胞分泌的ER蛋白平衡 不稳定的淀粉样蛋白，如TTR，直接影响它们的胞外聚集成有毒的 低聚物和淀粉样纤维与系统性淀粉样病的发病机制有关。在这里，我们将展示 肝脏ER蛋白平衡失衡促进细胞外聚集和外周毒性 淀粉样蛋白。这些结果将证明不同的遗传、环境或衰老相关 肝脏中影响ER蛋白平衡的因素可促进多发性肝合成的外周毒性 淀粉样蛋白，建立一个分子框架来解释肝脏在糖尿病中的临床重要性。 这些疾病的发病机制。此外，我们还将证明，通过增强肝脏中的ER蛋白平衡 内源性未折叠蛋白反应(UPR)相关信号通路的药理学激活 调节ER蛋白平衡提供了一种广泛适用的策略来改善细胞外分泌 多种淀粉样变蛋白的聚集和外周毒性。这些结果将确立 药理学UPR激活是治疗这类基本上无法治疗的癌症的新治疗机会 通过一种药物治疗疾病：多病治疗范式。

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.