Investigating the Effects of ADGRB3 Signaling on Incretin-Mediated Insulin Secretion from Pancreatic Beta-Cells
研究 ADGRB3 信号传导对肠促胰素介导的胰腺 β 细胞胰岛素分泌的影响
基本信息
- 批准号:10666206
- 负责人:
- 金额:$ 16.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2024-08-14
- 项目状态:已结题
- 来源:
- 关键词:Adenosine TriphosphateAdhesionsAdultAffectAgonistAngiogenesis InhibitorsBeta CellBindingBiological AssayBlood GlucoseBrainCalciumCalcium ChannelCalcium OscillationsCell membraneCell physiologyCellsCenters for Disease Control and Prevention (U.S.)ChronicCompensationComplement 1qCoupledCyclic AMPDataDevelopmentDiabetes MellitusDiseaseDockingEndocrineEpidemicEventExocytosisFailureFunctional disorderFutureG-Protein-Coupled ReceptorsGLP-I receptorGenesGenetic studyGlucoseGoalsHumanImageIndividualInsulinInsulin ResistanceIslet CellIslets of LangerhansKnowledgeLigandsLinkMediatingMetabolic DiseasesMissionMolecularMusMutationNon-Insulin-Dependent Diabetes MellitusObesityOutcomeOutputPersonsPharmaceutical PreparationsPharmacology StudyPhenotypePhysiologicalPopulationPrediabetes syndromePrevalenceProcessProductionProtein SecretionProteinsPublic HealthPublishingRoleSecond Messenger SystemsSignal TransductionSignaling MoleculeStructure of beta Cell of isletStudy modelsTestingTherapeuticThinnessTimeUnited StatesUnited States National Institutes of HealthWorkantagonistautocrinebrain cellcell typecomplement 1q receptordisorder riskdrug developmentexenatideexpectationfluorescence imagingglucagon-like peptide 1glucose metabolismimaging platformimprovedincretin hormoneinhibitorinnovationinsulin granuleinsulin secretionisletnew therapeutic targetnon-diabeticparacrineprotein expressionresponsetherapeutic targetvoltage
项目摘要
The prevalence of diabetes has reached epidemic proportions worldwide. According to the Centers for Disease
Control and Prevention, more than 37 million individuals in the US have diabetes (~10% of the adult population),
and another 84.1 million are prediabetic. Elevated blood sugar is the hallmark of diabetes, and insulin secreted
from the β-cells of the pancreatic islets is critical for maintaining proper blood sugar levels. It is currently accepted
that β-cell dysfunction is an early and essential event in the development of diabetes, including obesity-linked
type 2 diabetes (T2D). Cyclic AMP (cAMP) and ionic calcium (Ca2+) are key cellular signaling molecules that
stimulate β-cell insulin secretion. Ca2+ is the trigger for insulin secretion, while cAMP is required for the maximal
insulin secretion response. Preliminary data from our group suggests brain angiogenesis inhibitor-3 (BAI3: aka
ADGRB3), a G protein-coupled receptor for complement 1q like-3 secreted protein (C1ql3), may be a key player
in the β-cell dysfunction of T2D. BAI3 expression, and C1ql3 expression and secretion are both higher in
pancreatic islets from T2D mice and humans. BAI3 and C1ql3 are specifically expressed in islet β-cells and not
in other islet cell types. Finally, C1ql3 treatment reduces insulin secretion from islets stimulated by glucose and
drugs that raise β-cell Ca2+ or cAMP levels. Yet, the precise molecular mechanisms underlying β-cell C1ql3/BAI3
signaling, particularly in the pathophysiological states of obesity and T2D, remain uncharacterized. A full
understanding of these processes is required to achieve our long-term goal of discovering ways to modulate
BAI3 activity to improve or reverse the β-cell dysfunction of T2D. The overarching goal of this project, which is
the next logical step towards this goal, is to define BAI3 and C1ql3 levels, signaling mechanisms, and effects on
glucose-stimulated and cAMP-potentiated insulin secretion and how these change during β-cell compensation
for obesity and T2D β-cell failure. With our unique combination of scientific expertise and technically innovative
approaches, we are uniquely suited to complete this highly significant project. Tangible outcomes of the
proposed work are: i) revealing how BAI3 expression and C1ql3 expression and secretion change in response
to obesity and, ultimately, T2D; ii) quantifying the effects of BAI3 activation on β-cell Ca2+ influx and cAMP levels;
and iii) establishing how C1ql3-mediated BAI3 signaling inhibits glucose-stimulated and cAMP-potentiated
insulin secretion and the magnitude of its effects in the lean, obese, and T2D states. If successful, our work will
both define the signaling mechanisms downstream of BAI3, a poorly-characterized G protein-coupled receptor,
and provide strong preliminary data for future T2D drug development studies, leaving a high and long-lasting
impact on the field.
糖尿病的发病率在世界范围内已达到流行病的程度。根据疾病中心的数据
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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Sushant Bhatnagar其他文献
Sushant Bhatnagar的其他文献
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{{ truncateString('Sushant Bhatnagar', 18)}}的其他基金
Identifying secreted protein networks affecting human pancreatic islet function in type 2 diabetes using public omic databases
使用公共组学数据库识别影响 2 型糖尿病患者胰岛功能的分泌蛋白网络
- 批准号:
10372456 - 财政年份:2021
- 资助金额:
$ 16.41万 - 项目类别:
Identifying secreted protein networks affecting human pancreatic islet function in type 2 diabetes using public omic databases
使用公共组学数据库识别影响 2 型糖尿病患者胰岛功能的分泌蛋白网络
- 批准号:
10488268 - 财政年份:2021
- 资助金额:
$ 16.41万 - 项目类别:
The role of Tomosyn-2 in insulin secretion and glucose tolerance
Tomosyn-2在胰岛素分泌和葡萄糖耐量中的作用
- 批准号:
10348695 - 财政年份:2019
- 资助金额:
$ 16.41万 - 项目类别:
The role of Tomosyn-2 in insulin secretion and glucose tolerance
Tomosyn-2在胰岛素分泌和葡萄糖耐量中的作用
- 批准号:
10549803 - 财政年份:2019
- 资助金额:
$ 16.41万 - 项目类别:
The role of Tomosyn-2 in insulin secretion and glucose tolerance
Tomosyn-2在胰岛素分泌和葡萄糖耐量中的作用
- 批准号:
9913532 - 财政年份:2019
- 资助金额:
$ 16.41万 - 项目类别:
The role of Tomosyn-2 in insulin secretion and glucose tolerance
Tomosyn-2在胰岛素分泌和葡萄糖耐量中的作用
- 批准号:
10090593 - 财政年份:2019
- 资助金额:
$ 16.41万 - 项目类别:
THE ROLE OF TOMOSYN-2 IN INSULIN SECRETION
TomoSYN-2 在胰岛素分泌中的作用
- 批准号:
9411112 - 财政年份:2016
- 资助金额:
$ 16.41万 - 项目类别:
The role of tomosyn-2 in insulin secretion
Tomosyn-2在胰岛素分泌中的作用
- 批准号:
8916088 - 财政年份:2014
- 资助金额:
$ 16.41万 - 项目类别:
The role of tomosyn-2 in insulin secretion
Tomosyn-2在胰岛素分泌中的作用
- 批准号:
8766798 - 财政年份:2014
- 资助金额:
$ 16.41万 - 项目类别:
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