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

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(由申请方提供):胰腺炎是一种炎症性疾病,具有显著的健康和经济负担,缺乏预防复发或进展为慢性疾病的既定治疗。我们的长期目标是为这些疾病开发治疗方法。缺乏有效的治疗方法,部分原因是我们对胰腺炎的病理生理学了解有限。流行的胰蛋白酶依赖性模型认为,细胞内胰蛋白酶原激活和负责胰蛋白酶失活的保护机制的失败是发病机制的核心。尽管做了大量的努力,胰蛋白酶在胰腺炎中的作用仍然是推测性的,并且没有完全确定。最近的研究表明,外分泌蛋白突变、正常蛋白质稳态的破坏和ER过载途径的激活是患者疾病的另一种机制。因此,突变蛋白的表达对腺泡细胞是有毒的,并增加胰腺炎的风险。使用该模型,开发新疗法的方法将与基于胰蛋白酶依赖性模型的方法显著不同。在这里,我们解决的假设,羧基酯脂肪酶(CEL)突变体与慢性胰腺炎激活适应性细胞信号通路和细胞死亡途径,启动炎症反应,增加细胞对代谢应激损伤的敏感性。CEL突变发生在含有可变数量的富含脯氨酸的串联重复序列(VNTR)的区域。我们的初步数据表明,DEL变体在细胞内积累为聚集体并激活适应性细胞信号通路。我们提出了以下具体目的:1)确定用于处理CEL VNTR变体的不溶性聚集体的细胞途径; 2)鉴定通过表达CEL VNTR变体激活的适应性细胞信号传导途径; 3)确认我们在胰腺中表达CEL VNTR变体的小鼠模型中的离体结果。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,并提供针对新的治疗靶点蛋白质稳态的潜在药理学干预的见解。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

MARK E. LOWE其他文献

MARK E. LOWE的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.25万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了