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（申请人提供）：研究摘要全身性淀粉样蛋白疾病，例如甲状腺素蛋白（TTR）淀粉样蛋白是一类毁灭性疾病由特定不稳定蛋白作为淀粉样蛋白的病理聚集和沉积引起的距蛋白质合成部位远端的组织。目前，尚无无创疗法来治疗大多数在这些疾病中，使系统性淀粉样蛋白非常未满足医疗需求。定义的主要因素这些疾病的病理外蛋白质聚集是不稳定的，是不稳定的，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，浓度依赖性淀粉样蛋白蛋白的血清浓度聚集，直接影响患者的疾病发病机理。肝移植受者的临床结果表明降低淀粉样蛋白（如TTR）的血清浓度可以降低病理蛋白聚集，减弱外周蛋白毒性并改善患者的患者预后。我们假设激活调节蛋白质的内源性展开的蛋白质反应（UPR）信号通路从肝脏等效应组织的分泌是一种非侵入性策略，可以类似地降低分泌和减少可用于病理外细胞外的淀粉样蛋白蛋白的细胞外浓度聚合。与此预测一致，我们发现激活相关的转录因子ATF6减少了细胞培养模型中不稳定的淀粉样蛋白生成TTR突变体的分泌，但没有影响野生型TTR或内源性分泌蛋白质组的分泌。在这里，我们采用TTR作为模型淀粉样蛋白的蛋白质表明ATF6激活具有减少病理外细胞外的治疗潜力淀粉样蛋白生成TTR突变体的聚集和蛋白质毒性。对于这些实验，我们利用了小说患者衍生的多系统诱导的多能干细胞模型，促蛋白淀粉样蛋白疾病在患者中观察到的几乎所有TTR淀粉样蛋白疾病病理学的所有方面。通过这些努力，我们将展示 UPR相关信号通路（例如ATF6调节）的不依赖应力的激活是减少肝分泌，病理外部聚集和远端毒性的治疗策略与TTR相关淀粉样蛋白有关的淀粉样蛋白生成TTR变体的。建立这个模型蛋白TTR的方法将表明可以采用类似的策略来减轻与其他参与其他蛋白质的肝分泌和蛋白毒性细胞外聚集系统性淀粉样蛋白，揭示了一种新的治疗机会，可以广泛治疗这些毁灭性疾病。