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：
9304206
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/9304206
关键词：
ATF6 gene 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 Therapeutic Tissues Translating Transplant Recipients extracellular high throughput screening human disease improved induced pluripotent stem cell liver transplantation misfolded protein mutant novel outcome forecast primary amyloidosis of light chain type protein aggregation proteotoxicity public health relevance 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（由申请人提供）：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，由特定不稳定蛋白作为淀粉样原纤维在远离该部位的组织上病理性聚集和沉积而引起蛋白质合成。目前，还没有非侵入性疗法来治疗大多数这些疾病，这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。定义这些疾病的病理性细胞外蛋白聚集的主要因素是从效应组织（例如肝脏）分泌不稳定的淀粉样蛋白。这些蛋白质的有效分泌增加了可用于病理性、浓度依赖性聚集的淀粉样蛋白的血清浓度，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，降低淀粉样蛋白的血清浓度可以减少病理蛋白聚集，减轻外周蛋白毒性并改善患有各种不同系统性淀粉样变性的患者的预后。我们假设激活调节效应组织蛋白质分泌的内源性未折叠蛋白反应（UPR）信号通路是一种非侵入性策略，可同样减少分泌并降低可用于病理性细胞外聚集的淀粉样蛋白形成蛋白的细胞外浓度。与这一预测一致，我们发现激活 UPR 相关转录因子 ATF6 会减少不稳定的淀粉样变 TTR 突变体的分泌，但不会影响野生型 TTR 或内源分泌蛋白质组的分泌。在这里，我们采用 TTR 作为淀粉样蛋白形成模型，以证明 ATF6 激活具有治疗潜力，可减少淀粉样变性 TTR 突变体的病理性细胞外聚集和蛋白毒性，使用一种新型的患者来源、多系统诱导的 TTR 淀粉样蛋白疾病多能干细胞模型，该模型概括了 TTR 淀粉样蛋白疾病在患者中观察到 TTR 淀粉样蛋白疾病病理学的几乎所有方面。此外，我们扩展了这一分析，以表明 ATF6 激活同样会降低与其他系统性淀粉样蛋白疾病相关的淀粉样蛋白的分泌和蛋白毒性，包括轻链淀粉样变性——一种影响全球超过 100 万人的获得性系统性淀粉样蛋白疾病。通过这些努力，我们将证明UPR相关信号通路（例如由ATF6调节的信号通路）的应激独立激活是一种广泛适用的治疗策略，可减少与多种系统性淀粉样蛋白疾病相关的淀粉样蛋白的分泌和病理性细胞外聚集。这些结果将进一步激励我们正在进行的高通量筛选工作，以确定 ATF6 激活剂，因为单一小分子 ATF6 激活剂有可能治疗多种系统性淀粉样变性（即一种药物：多种疾病的治疗范例），从而显着提高治疗的经济性将选择性 ATF6 激活剂转化为临床，以改善与这些疾病相关的病理性细胞外聚集。