Control of beta cell function and survival by RYR2-mediated calcium signals

通过 RYR2 介导的钙信号控制 β 细胞功能和存活

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Despite the importance of β cell failure in the progression of diabetes (type 1, type 2, and multiple monogenic forms), the underlying molecular mechanisms responsible for β cell dysfunction remain incompletely understood. Release of insulin from the pancreatic β cell occurs in response to dynamic changes in cytosolic calcium (Ca2+) levels. To date, the majority of studies of β cell physiology have focused on the regulation of Ca2+ influx via plasma membrane ion channels, which have traditionally been more amenable to study via electrophysiological approaches. These studies have supported a dominant role for KATP channel-dependent plasma membrane depolarization and Ca2+ influx via voltage-gated Ca2+ channels in the regulation of insulin release, especially in response to very high concentrations of glucose. However, recent improvements in high temporal resolution imaging pioneered by our group have enabled the detection of robust Ca2+ signals in β cells stimulated with more physiologically relevant glucose concentrations, even in the absence of changes in plasma membrane potential, pointing to a critical role for the regulated release of Ca2+ from intracellular stores. In support of this, our published and preliminary data show that pharmacological manipulation of the activity of intracellular ryanodine receptors (RYR) uniquely modulates these ultrafast Ca2+ release events, even in voltage-clamp conditions, while also impacting glucose-stimulated insulin secretion. Together with other groups, we have found that the RYR2 isoform predominates in pancreatic β cells, and importantly showed using qRT-PCR and mass spectometry-based proteomics that RYR2 mRNA and protein can be identified in human and mouse islets and purified β cells. Furthermore, our preliminary data indicate that mice with β cell selective Ryr2 knockout have reduced insulin secretion and glucose intolerance, while ex vivo studies suggest that ER Ca2+ leak via dysregulated RYR activity leads to alterations in β cell Ca2+ signalling and accelerated β cell death. Against this background, we hypothesize that RYR2 channels serve as critical rheostats of β cell health and function and that they play key roles in diabetes progression. To test this hypothesis, we have assembled a multidisciplinary MPI team with expertise in β cell biology, diabetes physiology, quantitative imaging, and disease modelling, and three specific aims are proposed. In Specific Aim 1, we will quantify β cell RYR2 activity and roles in pancreatic slices and in vivo using intravital imaging. Specific Aim 2 will determine the in vivo role of β cell RYR2 in insulin secretion, β cell survival, and glucose homeostasis using a highly β cell-specific knockout mouse model. Specific Aim 3 will utilize mass spectrometry to determine mechanisms underlying ER stress-induced RYR2 dysfunction and in vitro and in vivo mouse models to define how ER stress-induced RYR2 dysfunction impacts β cell Ca2+ signaling and survival.
项目总结/文摘

项目成果

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Carmella Evans-Molina其他文献

Carmella Evans-Molina的其他文献

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{{ truncateString('Carmella Evans-Molina', 18)}}的其他基金

β cell miRNAs Function as Molecular Hubs of Type 1 Diabetes Pathogenesis
β 细胞 miRNA 作为 1 型糖尿病发病机制的分子中心
  • 批准号:
    10561855
  • 财政年份:
    2022
  • 资助金额:
    $ 45.3万
  • 项目类别:
β cell miRNAs Function as Molecular Hubs of Type 1 Diabetes Pathogenesis
β 细胞 miRNA 作为 1 型糖尿病发病机制的分子中心
  • 批准号:
    10321295
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
β cell miRNAs Function as Molecular Hubs of Type 1 Diabetes Pathogenesis
β 细胞 miRNA 作为 1 型糖尿病发病机制的分子中心
  • 批准号:
    10615586
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
Control of beta cell function and survival by RYR2-mediated calcium signals
通过 RYR2 介导的钙信号控制 β 细胞功能和存活
  • 批准号:
    10375087
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
Control of beta cell function and survival by RYR2-mediated calcium signals
通过 RYR2 介导的钙信号控制 β 细胞功能和存活
  • 批准号:
    10689291
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
Indiana University clinical Center for acute pancreatitis and diabetes clinical research network
印第安纳大学急性胰腺炎和糖尿病临床中心临床研究网络
  • 批准号:
    10458720
  • 财政年份:
    2020
  • 资助金额:
    $ 45.3万
  • 项目类别:
Indiana University clinical Center for acute pancreatitis and diabetes clinical research network
印第安纳大学急性胰腺炎和糖尿病临床中心临床研究网络
  • 批准号:
    10673629
  • 财政年份:
    2020
  • 资助金额:
    $ 45.3万
  • 项目类别:
Indiana University clinical Center for acute pancreatitis and diabetes clinical research network
印第安纳大学急性胰腺炎和糖尿病临床中心临床研究网络
  • 批准号:
    10265585
  • 财政年份:
    2020
  • 资助金额:
    $ 45.3万
  • 项目类别:
Islet Core
胰岛核心
  • 批准号:
    9105738
  • 财政年份:
    2016
  • 资助金额:
    $ 45.3万
  • 项目类别:
Indiana Diabetes Research Center
印第安纳州糖尿病研究中心
  • 批准号:
    10286616
  • 财政年份:
    2015
  • 资助金额:
    $ 45.3万
  • 项目类别:

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