UNDERSTANDING HEPATIC PROTEOSTASIS IN SYSTEMIC AMYLOID DISEASES
了解系统性淀粉样蛋白疾病中的肝脏蛋白质稳态
基本信息
- 批准号:10376880
- 负责人:
- 金额:$ 62.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-14 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATF6 geneAffectAgingAmyloid FibrilsAmyloidosisBiologicalCardiomyopathiesCell Culture TechniquesCellsClinicalDepositionDiagnosisDiseaseDisease modelDistalEndoplasmic ReticulumGeneticHeartHeart DiseasesHepaticHepatocyteHepatotoxicityIndividualKidneyKidney DiseasesLinkLiverLiver diseasesModelingMolecularMolecular ConformationMutationNeuropathyPathogenesisPathologicPathologyPathway interactionsPatientsPeripheralPeripheral NervesPharmaceutical PreparationsPharmacologyPhysiologicalPrealbuminPrevalenceProtein BiosynthesisProtein SecretionProteinsProteomicsPublishingRegulationRoleSerumSignal PathwaySignal TransductionSiteStressTherapeuticTissuesToxic effectVariantarmbasedefined contributionendoplasmic reticulum stressextracellularinduced pluripotent stem cellmouse modelnon-Nativenovelnovel therapeuticsproteostasisresponsetranscription factor
项目摘要
PROJECT SUMMARY
Systemic amyloid diseases are a class of disorders pathologically associated with the aggregation and
deposition of destabilized, amyloidogenic proteins on peripheral target tissues distal from the site of protein
synthesis such as the kidney, gut, heart, and peripheral nerves. Over 1 million individuals have been
diagnosed with these deadly diseases, although this is likely a significant underestimate of disease prevalence
as many undiagnosed renal and cardiac disorders are now being shown to involve systemic amyloid disease
pathology. Destabilizing mutations in over 15 different proteins, the majority of which are synthesized in the
liver, predispose individuals to systemic amyloid diseases. Since the pathology of these diseases is tightly
linked to the site of deposition, systemic amyloid diseases have traditionally been viewed as disorders of the
affected peripheral target tissues (e.g. renal disease, cardiomyopathy, and neuropathy). However, over the
past 10 years, significant clinical and biological evidence has revealed a critical role for the liver in dictating the
extracellular aggregation and deposition of amyloidogenic proteins. These results have challenged the
traditional view of systemic amyloid diseases and indicate that these disorders may be best viewed as
diseases of the liver. However, the mechanisms by which the liver contributes to systemic amyloid disease
pathogenesis remain poorly defined. Here, we hypothesize that imbalances in liver endoplasmic reticulum (ER)
protein homeostasis (or proteostasis) promotes the toxic extracellular aggregation of amyloidogenic proteins
implicated in systemic amyloid disease pathogenesis. Significant published results from our groups strongly
support a critical role for liver ER proteostasis in the toxic aggregation of liver-derived amyloidogenic proteins
such as transthyretin (TTR). We showed that disrupting or enhancing ER proteostasis in cells secreting
destabilized, amyloidogenic proteins such as TTR directly impacts their extracellular aggregation into toxic
oligomers and amyloid fibrils implicated in systemic amyloid disease pathogenesis. Here, we will show that
imbalances in liver ER proteostasis promotes the extracellular aggregation and peripheral toxicity of multiple
amyloidogenic proteins. These results will demonstrate that diverse genetic, environmental, or aging-related
factors that impact ER proteostasis in the liver can promote peripheral toxicity of multiple liver-synthesized
amyloidogenic proteins, establishing a molecular framework to explain the clinical importance of the liver in the
pathogenesis of these diseases. Furthermore, we will show that enhancing ER proteostasis in the liver through
pharmacologic activation of endogenous unfolded protein response (UPR)-associated signaling pathways that
regulate ER proteostasis offers a broadly-applicable strategy to ameliorate the secretion, extracellular
aggregation, and peripheral toxicity of multiple amyloidogenic proteins. These results will establish
pharmacologic UPR activation as a new therapeutic opportunity to treat this largely untreatable class of
disease through a one drug:multiple disease therapeutic paradigm.
项目摘要
系统性淀粉样蛋白疾病是一类与淀粉样蛋白聚集和变性有关的病理性疾病。
不稳定的淀粉样蛋白沉积在远离蛋白位点的外周靶组织上
肾脏、肠道、心脏和外周神经等合成系统。超过100万人被
被诊断出患有这些致命疾病,尽管这可能大大低估了疾病的患病率
因为许多未确诊的肾脏和心脏疾病现在被证明与系统性淀粉样蛋白疾病有关
病理超过15种不同蛋白质中的不稳定突变,其中大多数是在细胞中合成的。
肝脏,使个体易患系统性淀粉样蛋白疾病。由于这些疾病的病理学与
与沉积部位相关,系统性淀粉样蛋白疾病传统上被视为
受影响的外周靶组织(例如肾病、心肌病和神经病)。但在
在过去的10年里,重要的临床和生物学证据已经揭示了肝脏在决定肝脏功能方面的关键作用。
淀粉样蛋白的细胞外聚集和沉积。这些结果挑战了
系统性淀粉样蛋白疾病的传统观点,并表明这些疾病可能最好被视为
肝脏疾病。然而,肝脏导致系统性淀粉样疾病的机制
发病机制仍不明确。在这里,我们假设,肝内质网(ER)的不平衡,
蛋白质稳态促进淀粉样蛋白的毒性细胞外聚集
与系统性淀粉样蛋白疾病发病机制有关。我们的团队发表的重要结果强烈
支持肝脏ER蛋白质稳态在肝源性淀粉样蛋白毒性聚集中的关键作用
如甲状腺素运载蛋白(TTR)。我们发现,破坏或增强ER蛋白稳态的细胞分泌,
不稳定的淀粉样蛋白如TTR直接影响它们的细胞外聚集成毒性的
低聚物和淀粉样蛋白纤维参与系统性淀粉样蛋白疾病的发病机制。在这里,我们将表明,
肝脏ER蛋白质稳态的失衡促进了细胞外聚集和外周毒性,
淀粉样蛋白这些结果将表明,不同的遗传,环境,或衰老相关的
影响肝脏ER蛋白稳态的因素可促进多种肝脏合成的外周毒性,
淀粉样蛋白,建立一个分子框架,以解释肝脏在临床上的重要性,
这些疾病的发病机制。此外,我们将表明,增强ER蛋白在肝脏中的稳定,通过
内源性未折叠蛋白反应(UPR)相关信号通路的药理学激活,
调节ER蛋白质稳态提供了一个广泛适用的策略,以改善分泌,细胞外
聚集和多种淀粉样蛋白的外周毒性。这些结果将建立
药理学UPR激活作为一种新的治疗机会,以治疗这种基本上无法治疗的类型,
通过一种药物治疗多种疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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GEORGE J MURPHY其他文献
GEORGE J MURPHY的其他文献
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{{ truncateString('GEORGE J MURPHY', 18)}}的其他基金
UNDERSTANDING HEPATIC PROTEOSTASIS IN SYSTEMIC AMYLOID DISEASES
了解系统性淀粉样蛋白疾病中的肝脏蛋白质稳态
- 批准号:
10598011 - 财政年份:2020
- 资助金额:
$ 62.82万 - 项目类别:
UNDERSTANDING HEPATIC PROTEOSTASIS IN SYSTEMIC AMYLOID DISEASES
了解系统性淀粉样蛋白疾病中的肝脏蛋白质稳态
- 批准号:
10052855 - 财政年份:2020
- 资助金额:
$ 62.82万 - 项目类别:
UNDERSTANDING HEPATIC PROTEOSTASIS IN SYSTEMIC AMYLOID DISEASES
了解系统性淀粉样蛋白疾病中的肝脏蛋白质稳态
- 批准号:
10215499 - 财政年份:2020
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Mechanisms of cis-acting HbF regulation in sickle cell anemia
镰状细胞性贫血中顺式作用 HbF 调节机制
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9926298 - 财政年份:2017
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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
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8752486 - 财政年份:2014
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$ 62.82万 - 项目类别:
TARGETING ENDOGENOUS SIGNALING PATHWAYS TO AMELIORATE SYSTEMIC AMYLOIDOSES
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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
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9105178 - 财政年份:2014
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