Coordinated functions of ER quality control mechanisms in pancreatic islet α cells

胰岛α细胞ER质量控制机制的协调功能

基本信息

项目摘要

SUMMARY A central component of diabetes pathogenesis is dysregulated secretion of insulin and glucagon from b and α cells of the endocrine pancreas. Endocrine cells rely on protein quality control (QC) systems within the endoplasmic reticulum (ER) to clear misfolded proteins, maintain ER homeostasis and ensure hormone production. Misfolded proteins are removed in part through substrate-specific clearance by Sel1L-Hrd1 ER- associated degradation (ERAD), or bulk degradation of aggregates by autophagy. Our recent study showed that ERAD and autophagy regulate different aspects of β cell biology – maintenance of β cell identity and survival, respectively. Despite their shared importance in controlling glucose homeostasis, our understanding of α cell biology lags behind that of β cells. The mechanisms regulating ER homeostasis in (and thus, synthetic capacity of) α cells remain largely unexplored. To this end, mouse models lacking Sel1L-Hrd1 ERAD or autophagy in α cells were characterized. Defective ERAD limited glucagon production and α cell mass, but did not impair systemic glucagon secretion in response to hypoglycemia. In contrast, defective autophagy in α cells disrupted ER homeostasis and impaired glucagon secretion in vivo. Intriguingly, our preliminary data points to potential crosstalk between these two QC machineries. Hence, this proposal will test the overarching hypothesis that Sel1L-Hrd1 ERAD and autophagy cooperate to ensure ER proteostasis in pancreatic α cells – which is critical for α cell identity, function and/or survival. Using a combination of in vivo and in vitro genetic and pharmacologic approaches using mouse models, cell lines, and human islets, we will test the following Aims: (1) Demonstrate the pathophysiological importance of the interplay between ERAD and autophagy in α cells, and (2) Delineate the molecular mechanism underlying the crosstalk between ERAD and autophagy in α cells. This study will provide unprecedented insights into ER QC mechanisms in α cells, which may be harnessed to identify new therapeutic approaches to address α cell dysfunction in diabetes. This undertaking will build upon Dr. Reinert’s scientific expertise in developmental biology and physiology with training in two cutting-edge cell biology fields, ERAD and autophagy, with a focus on organelle crosstalk. Moreover, this study will strengthen Dr. Reinert’s technical skills by providing training in state-of-the-art cell biology techniques, thus paving a strong foundation for her future career as a physician scientist leading an interdisciplinary team studying islet cell biology and pathophysiology. This career development award will be overseen by three outstanding scientists and mentors Drs. Ling Qi, Peter Arvan, and Jiandie Lin at the University of Michigan.
概括 糖尿病发病机制的一个核心组成部分是β和α中胰岛素和胰高血糖素的分泌失调 内分泌胰腺细胞。内分泌细胞依赖于体内的蛋白质质量控​​制 (QC) 系统 内质网 (ER) 清除错误折叠的蛋白质,维持 ER 稳态并确保激素 生产。错误折叠的蛋白质通过 Sel1L-Hrd1 ER- 的底物特异性清除被部分去除 相关降解(ERAD),或通过自噬导致聚集体的大量降解。我们最近的研究表明 ERAD 和自噬调节 β 细胞生物学的不同方面——维持 β 细胞身份和 生存,分别。尽管它们在控制葡萄糖稳态方面具有共同的重要性,但我们的理解 α细胞生物学落后于β细胞。调节 ER 稳态的机制(因此,合成 α细胞的能力在很大程度上仍未被探索。为此,缺乏 Sel1L-Hrd1 ERAD 或 对 α 细胞的自噬进行了表征。有缺陷的 ERAD 限制了胰高血糖素的产生和 α 细胞质量,但确实 不损害响应低血糖的全身胰高血糖素分泌。相反,α 中的自噬缺陷 细胞破坏了内质网稳态并损害了体内胰高血糖素分泌。有趣的是,我们的初步数据 指出这两个 QC 机器之间存在潜在的串扰。因此,本提案将测试 总体假设是 Sel1L-Hrd1 ERAD 和自噬协同确保 ER 蛋白稳态 胰腺 α 细胞——对于 α 细胞的身份、功能和/或生存至关重要。结合使用 in 使用小鼠模型、细胞系和人类胰岛的体内和体外遗传和药理学方法,我们 将测试以下目标: (1) 证明 ERAD 之间相互作用的病理生理学重要性 和α细胞中的自噬,以及(2)描绘ERAD之间串扰的分子机制 和α细胞的自噬。这项研究将为 α 细胞中的 ER QC 机制提供前所未有的见解, 可以利用它来确定解决糖尿病α细胞功能障碍的新治疗方法。这 该项目将建立在 Reinert 博士在发育生物学和生理学方面的科学专业知识的基础上 ERAD 和自噬这两个前沿细胞生物学领域的培训,重点是细胞器串扰。 此外,这项研究将通过提供最先进的细胞培训来加强 Reinert 博士的技术技能 生物学技术,从而为她未来作为领导医学科学家的职业生涯奠定了坚实的基础 研究胰岛细胞生物学和病理生理学的跨学科团队。该职业发展奖将 由三位杰出科学家和导师 Drs 监督。凌奇、彼得·阿尔文和林建蝶在 密歇根大学。

项目成果

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Rachel Byerley Reinert其他文献

Rachel Byerley Reinert的其他文献

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{{ truncateString('Rachel Byerley Reinert', 18)}}的其他基金

Coordinated functions of ER quality control mechanisms in pancreatic islet α cells
胰岛α细胞ER质量控制机制的协调功能
  • 批准号:
    10450809
  • 财政年份:
    2021
  • 资助金额:
    $ 17.11万
  • 项目类别:
Coordinated functions of ER quality control mechanisms in pancreatic islet α cells
胰岛α细胞ER质量控制机制的协调功能
  • 批准号:
    10596137
  • 财政年份:
    2021
  • 资助金额:
    $ 17.11万
  • 项目类别:
Elucidating the Role of VEGF-A in Pancreatic Islet Innervation
阐明 VEGF-A 在胰岛神经支配中的作用
  • 批准号:
    7809361
  • 财政年份:
    2009
  • 资助金额:
    $ 17.11万
  • 项目类别:

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