Ion channel regulation of pancreatic islet cell function
离子通道对胰岛细胞功能的调节
基本信息
- 批准号:10249948
- 负责人:
- 金额:--
- 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:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAgingAnionsAttentionB Cell ProliferationB-LymphocytesBeta CellBiologyC-terminalCadaverCell membraneCell physiologyCellular biologyChloridesClosure by clampComplexCouplingCryoelectron MicroscopyDataDiabetes MellitusDiabetes preventionDiseaseEquilibriumExhibitsFRAP1 geneFailureGlucoseGlucose IntoleranceHealthHeart DiseasesHumanHyperglycemiaImmunoprecipitationImpairmentIn VitroInsulinIon ChannelIslets of LangerhansKidney DiseasesKnowledgeLabelLeucine-Rich RepeatLong-Term EffectsMass Spectrum AnalysisMeasuresMediatingMembrane PotentialsMicroscopyMissionModelingMolecularMorbidity - disease rateMusMutationNeuropathyNon-Insulin-Dependent Diabetes MellitusPathway interactionsPhasePopulationProtein FamilyProto-Oncogene Proteins c-aktReagentRegulationReportingResearchRetinal DiseasesSignal PathwaySignal TransductionSocietiesStrokeStructure of beta Cell of isletSwellingTestingTherapeuticTimeVesicleVeteranscell growthexperimental studygain of functionin vivoinnovationinsightinsulin secretioninsulin sensitivityisletknowledge basemembermilitary veteranmortalitymutantnovelnovel therapeutic interventionpatch clamppreservationtherapeutic targettraffickingvoltagevoltage clamp
项目摘要
Project Summary/Abstract
It is estimated that 1 in 4 Veterans suffer from diabetes, and, in the Veteran population, this is largely Type 2
diabetes. This condition drives heart disease, stroke, retinopathy, nephropathy and neuropathy, all of which
are a cause of significant morbidity and mortality among our Veterans. As such, understanding the biology of
diabetes, discovering novel molecules that regulate b-cell function and developing innovative therapeutic
approaches will have a significant impact on the health of our aging veteran population. Type 2 diabetes is
characterized by both a loss of insulin sensitivity and, ultimately, a relative loss of insulin-secretion from the
pancreatic b-cell. Insulin secretion from the pancreatic b-cell is triggered by Ca2+ influx through voltage-gated
Ca2+ channels (VGCC) to trigger insulin vesicle fusion with the b-cell plasma membrane.
We recently reported that SWELL1 (LRRC8a), a member of the Leucine Rich Repeat Containing protein
family, is required for ICl,SWELL in β-cells. SWELL1-mediated ICl,SWELL activates upon b-cell swelling induced by
glucose import, and this generates a depolarizing current contributing to VGCC activation, thereby regulating
insulin secretion and systemic glycemia. Indeed, mice with SWELL1-deficient β-cells exhibit impaired glucose-
stimulated insulin secretion and glucose intolerance. Moreover, we find that ICl,SWELL is reduced in both mouse
and humans in the context of Type 2 diabetes (T2D) indicating that reduced SWELL1 signaling is associated
with impaired b-cell function in T2D. The objective of the current proposal is to delineate the mechanisms by
which SWELL1 signaling regulates b-cell function, under basal conditions, and in the setting of Type 2
diabetes. Our central hypothesis is that SWELL1 regulates both glucose-stimulated insulin secretion and
PI3K-AKT-mTOR signaling in b-cells to maintain systemic glycaemia, and that impaired SWELL1
signaling contributes to b-cell failure in Type 2 diabetes. The contribution of this proposal is significant
because it explores the innovative concept the SWELL1 utilizes dual signaling domains (channel versus
LRRD) to regulate b-cell function in health and T2D. Importantly, this proposal will also define the relationship
between b-cell SWELL1 and T2D and test the notion that reduced SWELL1 signaling may drive impaired b-cell
function in T2D. We propose the following two AIMs:
AIM#1: Delineate the mechanism(s) of SWELL1-mediated regulation of excitation-secretion coupling.
AIM#2: Dissect the molecular mechanisms of SWELL1 macro-complex regulation of AKT-mTOR
signaling in b-cells.
The contribution of this proposal is innovative because it delineates a novel SWELL1 signaling pathway that
connects glucose-mediated b-cell swelling to b-cell depolarization and insulin-release - a form of b-cell swell-
activation or “swell-secretion” coupling. This proposal will enhance our understanding of b-cell biology and help
direct novel therapeutic approaches to b-cell failure in Type 2 diabetes.
!
项目总结/摘要
据估计,四分之一的退伍军人患有糖尿病,在退伍军人群体中,这主要是2型糖尿病。
糖尿病这种情况会导致心脏病、中风、视网膜病、肾病和神经病,
是我们退伍军人发病率和死亡率高的原因。因此,了解生物学
糖尿病,发现调节b细胞功能的新分子,开发创新的治疗方法
这些方法将对我们老年退伍军人的健康产生重大影响。2型糖尿病是
其特征在于胰岛素敏感性的丧失,并且最终,胰岛素分泌的相对丧失,
胰腺B细胞胰腺b细胞的胰岛素分泌是由Ca 2+通过电压门控的
Ca 2+通道(VGCC)触发胰岛素囊泡与b细胞质膜融合。
我们最近报道了SWELL 1(LRRC 8a),一个富含亮氨酸重复序列的蛋白,
家族,是β细胞中ICl、SWELL所必需的。SWELL 1介导的IC 1,SWELL在由
葡萄糖输入,并且这产生有助于VGCC激活的去极化电流,从而调节
胰岛素分泌和全身性炎症。事实上,SWELL 1缺陷β细胞的小鼠表现出葡萄糖代谢受损,
刺激胰岛素分泌和葡萄糖耐受不良。此外,我们发现,ICl,SWELL在两种小鼠中均降低,
2型糖尿病(T2 D)背景下的SWELL 1信号传导减少表明SWELL 1信号传导减少与糖尿病相关。
患有2型糖尿病的B细胞功能受损本提案的目的是通过以下方式界定这些机制:
在基础条件下和在类型2的设置中,SWELL 1信号传导调节b细胞功能
糖尿病我们的中心假设是SWELL 1调节葡萄糖刺激的胰岛素分泌,
PI 3 K-AKT-mTOR信号在b细胞中维持系统性高血压,并损害SWELL 1
信号传导导致2型糖尿病中的b细胞衰竭。这项建议的贡献是重大的
因为它探索了创新的概念,SWELL 1利用双信令域(信道与
LRRD)调节健康和T2 D中的B细胞功能。重要的是,该提案还将界定
在b细胞SWELL 1和T2 D之间,并测试减少的SWELL 1信号传导可能驱动受损的b细胞
T2 D功能我们提出以下两个目标:
目标#1:描述SWELL 1介导的兴奋-分泌偶联调节机制。
目的#2:剖析SWELL 1宏观复合物调节AKT-mTOR的分子机制
B细胞中的信号。
这项提议的贡献是创新的,因为它描绘了一种新的SWELL 1信号通路,
将葡萄糖介导的b细胞肿胀与b细胞去极化和胰岛素释放(b细胞肿胀的一种形式)联系起来,
活化或“溶胀-分泌”偶联。该提案将增强我们对b细胞生物学的理解,并有助于
2型糖尿病患者的B细胞衰竭的新的治疗方法。
!
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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Rajan Sah其他文献
Rajan Sah的其他文献
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{{ truncateString('Rajan Sah', 18)}}的其他基金
SWELL1-LRRC8 mediated regulation of skeletal muscle function and metabolism
SWELL1-LRRC8 介导的骨骼肌功能和代谢调节
- 批准号:
10618270 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Optimizing small molecule SWELL1-LRRC8 modulators to treat Type 2 diabetes
优化小分子 SWELL1-LRRC8 调节剂治疗 2 型糖尿病
- 批准号:
10216501 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Optimizing small molecule SWELL1-LRRC8 modulators to treat Type 2 diabetes
优化小分子 SWELL1-LRRC8 调节剂治疗 2 型糖尿病
- 批准号:
10430129 - 财政年份:2021
- 资助金额:
-- - 项目类别:
SWELL1-LRRC8 mediated regulation of skeletal muscle function and metabolism
SWELL1-LRRC8 介导的骨骼肌功能和代谢调节
- 批准号:
10454421 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Optimizing small molecule SWELL1-LRRC8 modulators to treat Type 2 diabetes
优化小分子 SWELL1-LRRC8 调节剂治疗 2 型糖尿病
- 批准号:
10617838 - 财政年份:2021
- 资助金额:
-- - 项目类别:
SWELL1-LRRC8 mediated regulation of skeletal muscle function and metabolism
SWELL1-LRRC8 介导的骨骼肌功能和代谢调节
- 批准号:
10305237 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Ion channel regulation of pancreatic islet cell function
离子通道对胰岛细胞功能的调节
- 批准号:
10477248 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Ion channel regulation of pancreatic islet cell function
离子通道对胰岛细胞功能的调节
- 批准号:
10664931 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Tuning fat cell size and obesity through SWELL1
通过 SWELL1 调节脂肪细胞大小和肥胖
- 批准号:
9917773 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Tuning Adipocyte Size and Obesity through SWELL1
通过 SWELL1 调节脂肪细胞大小和肥胖
- 批准号:
10649660 - 财政年份:2016
- 资助金额:
-- - 项目类别:
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