TARGETING ENDOGENOUS SIGNALING PATHWAYS TO AMELIORATE SYSTEMIC AMYLOIDOSES

描述(由申请人提供)：研究总结 全身性淀粉样病，如转甲状腺素(TTR)淀粉样变性，是一类破坏性疾病。 由特定的失稳蛋白病理性聚集和沉积引起的，如淀粉样纤维 蛋白质合成部位远端的组织。目前，还没有非侵入性疗法可以治疗大多数患者。 在这些疾病中，系统性淀粉样变性是一个巨大的未得到满足的医疗需求。一个主要因素定义了 病理性胞外蛋白聚集是这些疾病的核心是不稳定的分泌， 来自效应组织如肝脏的淀粉样蛋白。这些蛋白质的有效分泌 增加血清中可用于病理的淀粉样蛋白浓度，呈浓度依赖性 聚集性，直接影响疾病的发病机制。肝移植受者的临床结果 表明降低血清中淀粉样蛋白的浓度，如TTR，可以减少病理性蛋白 聚集，减轻外周蛋白毒性，改善患者预后。我们假设 激活调节蛋白质的内源性未折叠蛋白反应(UPR)信号通路 效应组织(如肝脏)的分泌是一种非侵入性策略，类似地减少分泌和 降低病理性胞外淀粉样蛋白的胞外浓度 聚合。与这一预测一致，我们发现激活UPR相关转录 在细胞培养模型中，ATF6因子减少不稳定的、淀粉样变性TTR突变体的分泌，但不会 影响野生型TTRs的分泌或内源性分泌的蛋白质组。在这里，我们使用Ttr作为模型 淀粉样蛋白显示ATF6激活具有减少病理性细胞外的治疗潜力 致淀粉样变Ttr突变体的聚集和蛋白毒性。对于这些实验，我们使用了一种新的 患者来源的多系统诱导的TTR淀粉样病多潜能干细胞模型 在患者中观察到了TTR淀粉样病病理的几乎所有方面。通过这些努力，我们将展示 与压力无关的UPR相关信号通路的激活，如ATF6调控的信号通路 是一种减少肝脏分泌物、病理性细胞外聚集和远端毒性的治疗策略 与TTR相关的淀粉样变性相关的导致淀粉样变性的TTR变异体。这个项目的建立 对于模型蛋白质TTR的方法将表明，可以使用类似的策略来减弱 肝脏分泌物和淀粉样蛋白原相关蛋白的胞外聚集 系统性淀粉样变性，揭示了广泛治疗这些破坏性疾病的新的治疗机会。

DESCRIPTION (provided by applicant): RESEARCH SUMMARY Systemic amyloid diseases such as the transthyretin (TTR) amyloidoses are a class of devastating disorders caused by the pathologic aggregation and deposition of specific destabilized proteins as amyloid fibrils on tissues distal from the site of protein synthesis. Currently, no non-invasive therapies exist to treat the majority of these diseases, making systemic amyloidoses a large unmet medical need. A primary factor defining the pathologic extracellular protein aggregation central to these disorders is the secretion of destabilized, amyloidogenic proteins from effector tissues such as the liver. The efficient secretion of these proteins increases serum concentrations of amyloidogenic protein available for pathologic, concentration-dependent aggregation, directly impacting disease pathogenesis in patients. Clinical results from liver transplant recipients show that reducing serum concentrations of amyloidogenic proteins like TTR can decrease pathologic protein aggregation, attenuate peripheral proteotoxicity and improve patient prognosis for patients. We hypothesize that activating the endogenous Unfolded Protein Response (UPR) signaling pathways that regulate protein secretion from effector tissues such as the liver is a non-invasive strategy to similarly decrease secretion and reduce extracellular concentrations of amyloidogenic proteins available for pathologic extracellular aggregation. Consistent with this prediction, we have found that activating the UPR- associated transcription factor ATF6 reduces secretion of destabilized, amyloidogenic TTR mutants in cell culture models, but does not affect the secretion of wild-type TTR or the endogenous secreted proteome. Here, we employ TTR as a model amyloidogenic protein to show that ATF6 activation has therapeutic potential to reduce pathologic extracellular aggregation and proteotoxicity of amyloidogenic TTR mutants. For these experiments, we utilize a novel patient-derived, multi- system induced pluripotent stem cell model of TTR amyloid disease that recapitulates nearly all aspects of TTR amyloid disease pathology observed in patients. Through these efforts, we will show that the stress-independent activation of UPR-associated signaling pathways such as that regulated by ATF6 is a therapeutic strategy to reduce the hepatic secretion, pathologic extracellular aggregation and distal toxicity of amyloidogenic TTR variants associated with the TTR-related amyloidoses. The establishment of this approach for the model protein TTR will suggest that a similar strategy could be applied to attenuate the hepatic secretion and proteotoxic extracellular aggregation of amyloidogenic proteins involved in other systemic amyloidoses, revealing a new therapeutic opportunity to broadly treat these devastating disorders.