Mechanism of JNK signaling in beta cells
β细胞中JNK信号传导机制
基本信息
- 批准号:10907873
- 负责人:
- 金额:$ 25.13万
- 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:2023-09-08 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAchievementAdipose tissueApoptosisB-LymphocytesBeta CellCell SurvivalCell physiologyCellular StressChronicConsumptionDataDevelopmentDiabetes MellitusFailureFunctional disorderGenesGenetic Complementation TestGoalsHealthHigh Fat DietHomeostasisHumanHyperglycemiaHyperinsulinismHyperlipidemiaIn VitroIndividualInsulin ResistanceJUN geneKnockout MiceKnowledgeLinkLiverMAPK8 geneMediatingMediatorMetabolicMetabolic dysfunctionMetabolic stressMetabolic syndromeMolecularMusMuscleNon-Insulin-Dependent Diabetes MellitusNutrientObesityPathogenesisPeripheralPersonsPharmaceutical PreparationsPhysiologicalPhysiologyPlayPrevalencePreventionRegulationReportingResearchResearch DesignRoleSignal PathwaySignal TransductionStressTestingTissuesbiological adaptation to stressblood glucose regulationcell typecytokinedesigndrug developmentimprovedin vivo Modelinsulin secretionnew therapeutic targetnovel strategiesnovel therapeutic interventionprogramstreatment strategy
项目摘要
Project Summary
Diabetes mellitus represents a serious world-wide health problem. The prevalence of diabetes mellitus is
predicted to increase from 451 million people in 2017 to 693 million people in 2045. More than 90% of individuals
with diabetes mellitus have type 2 diabetes. The pathogenesis of type 2 diabetes is closely linked to obesity and
metabolic syndrome that are associated with insulin resistance, chronic hyperglycemia, and hyperlipidemia that
promote progressive b cell dysfunction and b cell failure. Several medications are currently under development,
including approaches to improve b cell function and survival. Nevertheless, there is an unmet need for the
development of effective and safe therapies. Therefore, the identification of novel targets for drug development
requires that we gain an understanding the physiology and pathophysiology of b cells with metabolic dysfunction.
Nutrient excess can result in metabolic dysfunction and b cell stress. Recent studies have identified the c-Jun
NH2-terminal kinase (JNK) signaling pathway as a mediator of metabolic stress responses. Consumption of a
high-fat diet (HFD) causes increased JNK activity and promotes the development of metabolic syndrome, such
as obesity, hyperglycemia, and insulin resistance. The role of JNK in metabolic tissues has been studied using
cell type-specific JNK knockout mice. These studies demonstrate that JNK deficiency in peripheral metabolic
tissues suppresses HFD-induced hyperglycemia and hyperinsulinemia. However, while the role of JNK in these
peripheral tissues has been extensively studied, the function of b cell JNK in physiology and pathogenesis
remains unclear. Nevertheless, it has been reported that JNK inhibition increases insulin secretion and protects
against cytokine-induced b cell apoptosis in vitro. However, the role of JNK in b cell physiology has not been
studied using an in vivo model with b cell-specific Jnk gene ablation. Our preliminary data show that JNK in b
cells plays an important role in the regulation of b cell mass, insulin secretion, and glucose homeostasis in mice
fed a HFD. Therefore, JNK plays a critical role in metabolic stress-induced b cell pathogenesis.
Knowledge of the mechanism of HFD-induced b cell dysfunction is important because it is likely that insulin
resistance may promote hyperglycemia, hyperinsulinemia and subsequent b cell failure during progression from
metabolic syndrome to type 2 diabetes. Studies designed to examine the mechanism of JNK-dependent b cell
dysfunction caused by consumption of a HFD are therefore significant because the knowledge obtained may be
useful for the design new therapeutic strategies for the treatment and prevention of type 2 diabetes.
We will examine the role of JNK signaling using mice with b cell-specific ablation of the Jnk genes and we will
identify the JNK-dependent regulatory mechanisms that control b cell function. Achievement of our goals will
increase understanding of how metabolic stress signaling contributes b cell physiology and pathophysiology. We
anticipate that the successful completion of this research program will lead to the identification of mechanisms
that regulates b cell homeostasis.
项目总结
项目成果
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