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.
项目摘要
糖尿病是一个严重的世界性健康问题。糖尿病的患病率是
预计将从2017年的4.51亿人增加到2045年的6.93亿人。超过90%的个人
有糖尿病的人有2型糖尿病。2型糖尿病的发病机制与肥胖和
与胰岛素抵抗、慢性高血糖和高脂血症相关的代谢综合征
促进进行性b细胞功能障碍和b细胞衰竭。目前有几种药物正在研发中,
包括改善B细胞功能和存活率的方法。然而,仍有一种未得到满足的需求
开发有效和安全的治疗方法。因此,确定药物开发的新靶点
要求我们了解代谢障碍的b细胞的生理学和病理生理学。
营养过剩会导致代谢功能障碍和b细胞应激。最近的研究已经确定了c-jun
NH2-末端激酶(JNK)信号通路作为代谢应激反应的中介。消费
高脂饮食(HFD)会导致JNK活性增加,并促进代谢综合征的发展,如
如肥胖、高血糖和胰岛素抵抗。JNK在新陈代谢组织中的作用已经通过
细胞类型特异的JNK基因敲除小鼠。这些研究表明,外周代谢中的JNK缺乏
组织抑制HFD引起的高血糖和高胰岛素血症。然而,虽然JNK在这些方面的作用
外周组织已被广泛研究,b细胞jnk在生理和发病机制中的作用。
目前仍不清楚。然而,据报道,抑制JNK可以增加胰岛素的分泌并保护
体外抗细胞因子诱导的b细胞凋亡。然而,jnk在b细胞生理学中的作用尚未得到证实。
使用b细胞特异性jnk基因消融的体内模型进行研究。我们的初步数据显示,jnk在b
细胞在调节小鼠的b细胞质量、胰岛素分泌和葡萄糖稳态方面起着重要作用。
喂了一只HFD。因此,JNK在代谢应激诱导的B细胞发病机制中起关键作用。
了解HFD诱导的B细胞功能障碍的机制很重要,因为胰岛素很可能
抵抗可能促进高血糖、高胰岛素血症和随后的b细胞衰竭。
代谢综合征转变为2型糖尿病。旨在研究JNK依赖的b细胞的机制的研究
因此,食用HFD导致的功能障碍是显著的,因为所获得的知识可能是
有助于为2型糖尿病的治疗和预防设计新的治疗策略。
我们将使用b细胞特异性的jnk基因消融的小鼠来研究jnk信号的作用,我们将
确定控制b细胞功能的依赖jnk的调节机制。实现我们的目标将会
增加对代谢应激信号如何影响b细胞生理学和病理生理学的理解。我们
预计这项研究计划的成功完成将导致机制的确定
来调节b细胞的动态平衡。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Myoungsook Han其他文献
Myoungsook Han的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335802 - 财政年份:2024
- 资助金额:
$ 25.13万 - 项目类别:
Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335801 - 财政年份:2024
- 资助金额:
$ 25.13万 - 项目类别:
Standard Grant
A Longitudinal Study of the Relationship between Participation in a Comprehensive Exercise Program and Academic Achievement
参加综合锻炼计划与学业成绩之间关系的纵向研究
- 批准号:
24K14615 - 财政年份:2024
- 资助金额:
$ 25.13万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Collaborative Research: Characterizing Best Practices of Instructors who Have Narrowed Performance Gaps in Undergraduate Student Achievement in Introductory STEM Courses
合作研究:缩小本科生 STEM 入门课程成绩差距的讲师的最佳实践
- 批准号:
2420369 - 财政年份:2024
- 资助金额:
$ 25.13万 - 项目类别:
Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335800 - 财政年份:2024
- 资助金额:
$ 25.13万 - 项目类别:
Standard Grant
WTG: Diffusion of Research on Supporting Mathematics Achievement for Youth with Disabilities through Twitter Translational Visual Abstracts
WTG:通过 Twitter 翻译视觉摘要传播支持残疾青少年数学成就的研究
- 批准号:
2244734 - 财政年份:2023
- 资助金额:
$ 25.13万 - 项目类别:
Standard Grant
The Impact of Emotional Experiences of Pride on Long-Term Goal Achievement Behaviors in Elite Athletes
骄傲的情感体验对优秀运动员长期目标实现行为的影响
- 批准号:
23K16740 - 财政年份:2023
- 资助金额:
$ 25.13万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Meta-Analysis of the Instructional-Relational Model of Student Engagement and Math Achievement: A Moderation and Mediation Approach
学生参与度和数学成绩的教学关系模型的元分析:一种调节和中介方法
- 批准号:
2300738 - 财政年份:2023
- 资助金额:
$ 25.13万 - 项目类别:
Standard Grant
Improving maths achievement in children with speech, language, and communication needs through 'collaborative vocabulary teaching'
通过“协作词汇教学”提高有言语、语言和交流需求的儿童的数学成绩
- 批准号:
2890475 - 财政年份:2023
- 资助金额:
$ 25.13万 - 项目类别:
Studentship
HSI Institutional Transformation Project: Retention and Achievement for Introductory STEM English Learners (RAISE)
HSI 机构转型项目:STEM 英语入门学习者的保留和成就 (RAISE)
- 批准号:
2225178 - 财政年份:2023
- 资助金额:
$ 25.13万 - 项目类别:
Continuing Grant