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TARGETING ENDOGENOUS SIGNALING PATHWAYS TO AMELIORATE SYSTEMIC AMYLOIDOSES

靶向内源信号传导途径以改善系统性淀粉样变

基本信息

批准号：
8752486
负责人：
GEORGE J MURPHY
金额：
$ 22.15万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-08 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8752486
关键词：
Affect Amyloid Amyloid Fibrils Amyloidosis Animal Model Apolipoprotein A-I Attenuated Biological Assay Cell model Cells Clinic Clinical Deposition Disease Disease model Dissociation Distal Economics Extracellular Protein Gel Chromatography Genetic Goals Hepatic Individual Ligands Light-Chain Immunoglobulins Liver Mammalian Cell Measures Medical Modeling Outcome Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Prealbumin Protein Biosynthesis Protein Secretion Proteins Proteome Publishing Resources Serum Signal Pathway Site Stress System Therapeutic Tissues Translating Transplant Recipients extracellular high throughput screening human disease improved induced pluripotent stem cell liver transplantation meetings mutant novel outcome forecast primary amyloidosis of light chain type protein aggregation public health relevance response small molecule transcription factor ATF6

项目摘要

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.

描述（由申请人提供）：研究摘要系统性淀粉样蛋白疾病，例如转甲状腺素蛋白 (TTR) 淀粉样变性是一类破坏性疾病由淀粉样原纤维等特定不稳定蛋白质的病理性聚集和沉积引起远离蛋白质合成位点的组织。目前，没有非侵入性疗法可以治疗大多数患者这些疾病的存在，使得系统性淀粉样变性成为一个巨大的未满足的医疗需求。定义的主要因素这些疾病的核心病理性细胞外蛋白聚集是不稳定的分泌，来自效应组织（例如肝脏）的淀粉样蛋白。这些蛋白质的有效分泌增加可用于病理学、浓度依赖性的淀粉样蛋白的血清浓度聚集，直接影响患者的疾病发病机制。肝移植受者的临床结果表明降低淀粉样蛋白（如 TTR）的血清浓度可以减少病理蛋白聚集，减弱外周蛋白毒性并改善患者的预后。我们假设激活调节蛋白质的内源性未折叠蛋白反应 (UPR) 信号通路从效应组织（例如肝脏）分泌是一种非侵入性策略，同样可以减少分泌和减少可用于病理性细胞外的淀粉样蛋白的细胞外浓度聚合。与这一预测一致，我们发现激活 UPR 相关转录 ATF6 因子可减少细胞培养模型中不稳定的淀粉样蛋白 TTR 突变体的分泌，但不会减少影响野生型TTR或内源分泌蛋白质组的分泌。这里，我们使用TTR作为模型淀粉样蛋白生成表明 ATF6 激活具有减少病理性细胞外损伤的治疗潜力淀粉样蛋白 TTR 突变体的聚集和蛋白毒性。对于这些实验，我们利用了一种新颖的患者来源的多系统诱导的 TTR 淀粉样蛋白病多能干细胞模型，概括了在患者中观察到 TTR 淀粉样蛋白疾病病理学的几乎所有方面。通过这些努力，我们将展示 UPR 相关信号通路（如 ATF6 调节的信号通路）的应激独立激活是一种减少肝脏分泌、病理性细胞外聚集和远端毒性的治疗策略与 TTR 相关淀粉样变性相关的淀粉样变 TTR 变体。本次的设立模型蛋白 TTR 的方法表明可以应用类似的策略来减弱与其他相关的淀粉样蛋白的肝分泌和蛋白毒性细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治疗机会。