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：
9105178
负责人：
GEORGE J MURPHY
金额：
$ 20.06万
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/9105178
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 Goals Health Hepatic Individual Ligands Light-Chain Immunoglobulins Liver Mammalian Cell Measures Medical Medical Genetics 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 response small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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 can decrease pathologic protein aggregation, attenuate peripheral proteotoxicity and improve prognosis for patients presenting with a variety of distinct systemic amyloidoses. We hypothesize that activating the endogenous Unfolded Protein Response (UPR) signaling pathways that regulate protein secretion from effector tissues 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 show that activating the UPR- associated transcription factor ATF6 reduces secretion of destabilized, amyloidogenic TTR mutants, 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 using 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. Furthermore, we are extending this analysis to show that ATF6 activation similarly reduces the secretion and proteotoxicity of amyloidogenic proteins involved in other systemic amyloid diseases including Light Chain Amyloidosis - an acquired systemic amyloid disease that affects >1 million individuals worldwide. Through these efforts, we will show that the stress-independent activation of UPR-associated signaling pathways such as that regulated by ATF6 is a broadly-applicable therapeutic strategy to reduce the secretion and pathologic extracellular aggregation of amyloidogenic proteins associated with multiple systemic amyloid diseases. These results will further motivate our ongoing high- throughput screening efforts to identify ATF6 activators, as a single small molecule ATF6 activator has the potential to treat multiple systemic amyloidoses (i.e. a one-drug:multiple-disease therapeutic paradigm) dramatically improving the economics of translating selective ATF6 activators into the clinic to ameliorate pathologic extracellular aggregation associated with these diseases.

描述（申请人提供）：全身性淀粉样蛋白疾病，例如甲状腺素蛋白（TTR）淀粉样蛋白是一类是由一类毁灭性疾病，由病理聚集和特定不稳定蛋白的病理聚集和沉积，将特定稳定蛋白作为淀粉样蛋白作为来自现场的淀粉样蛋白的淀粉样蛋白的，蛋白质合成。当前，尚无无创疗法来治疗大多数这些疾病，从而使系统性淀粉样蛋白非常未满足医疗需求。定义这些疾病中心的病理外蛋白聚集的主要因素是从肝脏等效应组织（例如肝脏组织）分泌不稳定的淀粉样蛋白蛋白。这些蛋白质的有效分泌增加了可用于病理，浓度依赖性聚集的淀粉样生成蛋白的血清浓度，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，降低淀粉样蛋白蛋白的血清浓度可以减少病理蛋白的聚集，减轻外周蛋白蛋白毒性并改善出现各种不同全身性淀粉样蛋白的患者的预后。我们假设激活内源性展开的蛋白质反应（UPR）信号通路，从效应组织调节蛋白质的分泌是一种非侵入性策略，可以类似地降低分泌并降低细胞外浓度的淀粉样蛋白蛋白，可用于病理外细胞外聚集。与该预测一致，我们表明激活相关的转录因子ATF6降低了不稳定的，淀粉样蛋白酶生成的TTR突变体的分泌，但不会影响野生型TTR或内源性分泌蛋白质组的分泌。在这里，我们采用TTR作为淀粉样生成蛋白的模型表明，ATF6激活具有治疗潜力，可减少淀粉样蛋白生成TTR突变体的病理性细胞外聚集和蛋白毒性，并使用一种新型的患者衍生的，多系统诱导的多能性多能性干细胞模型的TTR淀粉样蛋白疾病模型的病理几乎可以促成各种方面的ttry Amparss trems trys ttrys ttrys trys ttry am ttr。此外，我们正在扩展这项分析，以表明ATF6激活类似地降低了参与其他系统性淀粉样蛋白涉及的淀粉样蛋白蛋白的分泌和蛋白质毒性，包括轻链淀粉样蛋白 - 一种获得的全身性淀粉样蛋白疾病，影响了全球> 100万个个体。通过这些努力，我们将证明与UPR相关的信号传导途径（例如由ATF6调节的）激活是一种广泛适用的治疗策略，旨在减少与多种全身性淀粉样蛋白疾病相关的淀粉样蛋白的分泌和病理外部淀粉样蛋白的细胞外聚集。 These results will further motivate our ongoing high- throughput screening efforts to identify ATF6 activators, as a single small molecule ATF6 activator has the potential to treat multiple systemic amyloidoses (i.e. a one-drug:multiple-disease therapeutic paradigm) dramatically improving the economics of translating selective ATF6 activators into the clinic to ameliorate pathologic extracellular aggregation associated with these diseases.