Proteotoxicity in the Pathophysiology of Chronic Pancreatitis
慢性胰腺炎病理生理学中的蛋白质毒性
基本信息
- 批准号:8838103
- 负责人:
- 金额:$ 33.25万
- 依托单位:
- 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:2014-04-15 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acinar CellAddressApoptosisAutophagocytosisCell DeathCell Death Signaling ProcessCellsChronic DiseaseClinicalDataDegradation PathwayDevelopmentDiseaseEconomic BurdenEnzymesEstersFailureFigs - dietaryFunctional disorderGoalsHealthHomeostasisInflammationInflammatoryInflammatory ResponseInjuryInterventionKnowledgeLipaseMAPK8 geneMeasuresMetabolic stressMinisatellite RepeatsModelingMolecularMusMutationNaturePancreasPancreatic InjuryPancreatitisPathogenesisPathway interactionsPatientsPredispositionProcessProlineProteinsRecurrenceReportingRiskRoleSignal PathwaySignal TransductionStressTandem Repeat SequencesTrypsinTrypsinogenVariantacute pancreatitisbasebiological adaptation to stresscell injurychronic pancreatitisdisulfide bondeffective therapygain of functionhealth economicsimprovedin vivoinsightmouse modelmulticatalytic endopeptidase complexmutantnew therapeutic targetnovelnovel therapeuticspatient populationpreventprotein aggregateresponsestemtherapy development
项目摘要
DESCRIPTION (provided by applicant): Pancreatitis is an inflammatory disease with significant health and economic burdens that lacks an established therapy to prevent recurrent episodes or progression to chronic disease. Our long-term goal is to develop therapies for these diseases. The absence of effective therapies stems in part from our limited understanding about the pathophysiology of pancreatitis. The prevailing trypsin-dependent model holds that intracellular trypsinogen activation and failure of protective mechanisms responsible for trypsin inactivation are central to pathogenesis. Despite great effort the role of trypsin in pancreatitis remains speculative and incompletely defined. Recent studies suggest another mechanism for disease in patients with mutations in exocrine proteins, disruption of normal protein homeostasis and activation of ER overload pathways. As a result, expression of the mutant proteins is toxic to acinar cells and increases the risk for pancreatitis. With this model, the approach to developing new therapeutics would differ significantly from approaches based on the trypsin-dependent model. Herein, we address the hypothesis that carboxyl ester lipase (CEL) mutants associated with chronic pancreatitis activate adaptive cell signaling pathways and cell death pathways, initiate an inflammatory response and increase susceptibility of cells to injury by metabolic stress. The CEL mutations occur in the region containing a variable number of proline-rich tandem repeats (VNTR). Our preliminary data show that the DEL variants accumulate within the cells as aggregates and activate adaptive cell signaling pathways. We propose the following Specific Aims: 1) Determine the cellular pathways for the disposal of insoluble aggregates of CEL VNTR variants; 2) Identify the adaptive cell signaling pathways activated by expression of CEL VNTR variants; 3) Confirm our ex vivo results in mouse models that express CEL VNTR variants in the pancreas. The knowledge gained by the proposed studies will improve the overall understanding of pancreatic injury and provide insight into potential pharmacological interventions directed at a new therapeutic target, protein homeostasis.
描述(申请人提供):胰腺炎是一种炎症性疾病,具有重大的健康和经济负担,缺乏既定的治疗方法来防止复发或进展为慢性病。我们的长期目标是开发这些疾病的治疗方法。缺乏有效的治疗方法的部分原因是我们对胰腺炎的病理生理学了解有限。目前流行的胰酶依赖模型认为,细胞内胰酶原的激活和导致胰酶失活的保护机制的失效是发病的核心。尽管做了很大的努力,但胰酶在胰腺炎中的作用仍然是推测的,也不完全确定。最近的研究表明,外分泌蛋白突变、正常蛋白质动态平衡中断和ER过载途径激活的患者的另一种疾病机制。因此,突变蛋白的表达对腺泡细胞是有毒的,并增加了患胰腺炎的风险。有了这个模型,开发新疗法的方法将与基于胰酶依赖模型的方法有很大不同。在此,我们提出了一种假设,即与慢性胰腺炎相关的羧基酯脂肪酶(CEL)突变激活了适应性细胞信号通路和细胞死亡通路,启动了炎症反应,增加了细胞对代谢应激损伤的易感性。CEL突变发生在含有数量可变的富含脯氨酸的串联重复序列(VNTR)的区域。我们的初步数据显示,Del变异体以聚集体的形式在细胞内积累,并激活适应性细胞信号通路。我们提出了以下具体目标:1)确定处理CEL VNTR变体不溶性聚集体的细胞途径;2)确定CEL VNTR变体表达激活的适应性细胞信号通路;3)在胰腺表达CEL VNTR变体的小鼠模型中证实我们的体外结果。通过拟议的研究获得的知识将提高对胰腺损伤的整体理解,并为针对新的治疗目标--蛋白质稳态提供潜在的药物干预提供洞察力。
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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MARK E. LOWE其他文献
MARK E. LOWE的其他文献
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{{ truncateString('MARK E. LOWE', 18)}}的其他基金
Year 7 Administrative Supplement to INSPPIRE 2
INSPPIRE 2 的第 7 年行政补充
- 批准号:
10469779 - 财政年份:2021
- 资助金额:
$ 33.25万 - 项目类别:
Does Proteotoxicity Contribute to Chronic Pancreatitis in Murine Models of Human Carboxyl Ester Lipase (CEL) Genetic Risk Variants?
在人羧基酯脂肪酶 (CEL) 遗传风险变异小鼠模型中,蛋白质毒性是否会导致慢性胰腺炎?
- 批准号:
10541891 - 财政年份:2020
- 资助金额:
$ 33.25万 - 项目类别:
Does Proteotoxicity Contribute to Chronic Pancreatitis in Murine Models of Human Carboxyl Ester Lipase (CEL) Genetic Risk Variants?
在人羧基酯脂肪酶 (CEL) 遗传风险变异小鼠模型中,蛋白质毒性是否会导致慢性胰腺炎?
- 批准号:
10328254 - 财政年份:2020
- 资助金额:
$ 33.25万 - 项目类别:
INSPPIRE: A Longitudinal Cohort Study of Pediatric Chronic Pancreatitis to Predict Clinical Course and Identify Disease Modifiers
INSPPIRE:儿科慢性胰腺炎的纵向队列研究,用于预测临床病程并确定疾病调节因子
- 批准号:
10657692 - 财政年份:2015
- 资助金额:
$ 33.25万 - 项目类别:
INSPPIRE: A Longitudinal Cohort Study of Pediatric Chronic Pancreatitis to Predict Clinical Course and Identify Disease Modifiers
INSPPIRE:儿科慢性胰腺炎的纵向队列研究,用于预测临床病程并确定疾病调节因子
- 批准号:
10684450 - 财政年份:2015
- 资助金额:
$ 33.25万 - 项目类别:
INSPPIRE: A Longitudinal Cohort Study of Pediatric Chronic Pancreatitis to Predict Clinical Course and Identify Disease Modifiers
INSPPIRE:儿科慢性胰腺炎的纵向队列研究,用于预测临床病程并确定疾病调节因子
- 批准号:
10445080 - 财政年份:2015
- 资助金额:
$ 33.25万 - 项目类别:
INSPPIRE: A Longitudinal Cohort Study of Pediatric Chronic Pancreatitis to Predict Clinical Course and Identify Disease Modifiers
INSPPIRE:儿科慢性胰腺炎的纵向队列研究,用于预测临床病程并确定疾病调节因子
- 批准号:
10263563 - 财政年份:2015
- 资助金额:
$ 33.25万 - 项目类别:
INSPPIRE: A Longitudinal Cohort Study of Pediatric Chronic Pancreatitis to Predict Clinical Course and Identify Disease Modifiers
INSPPIRE:儿科慢性胰腺炎的纵向队列研究,用于预测临床病程并确定疾病调节因子
- 批准号:
10252050 - 财政年份:2015
- 资助金额:
$ 33.25万 - 项目类别:
Proteotoxicity in the Pathophysiology of Chronic Pancreatitis
慢性胰腺炎病理生理学中的蛋白质毒性
- 批准号:
8627251 - 财政年份:2014
- 资助金额:
$ 33.25万 - 项目类别:
Basic/Translational Research Training for CHP Pediatric Fellows
卫生防护中心儿科研究员基础/转化研究培训
- 批准号:
8843907 - 财政年份:2013
- 资助金额:
$ 33.25万 - 项目类别:
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