microRNA-483 regulation of pancreatic beta-cell function and identity
microRNA-483 对胰腺 β 细胞功能和身份的调节
基本信息
- 批准号:10580237
- 负责人:
- 金额:$ 40.43万
- 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:2023-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAlpha CellAntioxidantsAvena sativaBeta CellBiochemistryCYP2E1 geneCell DeathCell Differentiation processCell SurvivalCell physiologyCellsClinicalDataDevelopmentDiabetes MellitusDietDown-RegulationEducationEligibility DeterminationEndocrineEnzymesExhibitsFailureFundingGamma-glutamyl transferaseGene ExpressionGenesGlucagonGoalsHigh Fat DietHumanHyperglycemiaImpairmentInstitutionInsulinInsulin ResistanceLaboratoriesLinkMetabolic DiseasesMetabolic stressMichiganMicroRNAsMitochondriaMolecular BiologyMusNon-Insulin-Dependent Diabetes MellitusOxidative StressPathway interactionsPatientsPhysiologyProcessRegulationReporterResearchResearch InfrastructureRoleScienceStressStructure of beta Cell of isletSystemTechnologyTestingTherapeuticUniversitiesUntranslated RNAUp-Regulationbiological adaptation to stresscell dedifferentiationcell typediabetes mellitus therapydiabetes pathogenesisdiabeticfeedingfunctional lossglucose tolerancegraduate studentinsightisletmid-career facultymitochondrial dysfunctionnovelnovel therapeutic interventionoxidationpreventprogenitorprogramstranscription factortranscriptome sequencingtransdifferentiationtreatment strategyundergraduate student
项目摘要
Abstract:
Type 2 diabetes is a metabolic disorder that causes hyperglycemia in patients. Loss of functional
beta-cell mass is a hallmark of progression from insulin resistance to overt diabetes. New
evidence indicated altered identity of β-cells due to beta-cell dedifferentiation is believed to be a
new mechanism of β-cell loss in diabetes. However, the mechanism of β-cell dedifferentiation
remains to be investigated. microRNAs (miRNAs) are small non-coding RNAs that regulate β-
cell function and survival by inhibiting specific target gene expression. We discovered that miR-
483 is highly expressed in β-cells, but much less in α-cells. Mice with β-cell specific deletion of
miR-483 exhibited diet-induced hyperglycemia and reduced glucose tolerance without changing
in β-cell mass. RNA-seq analysis revealed that miR-483 inactivation resulted in a marked increase
in oxidative stress markers including gamma-glutamyltransferase (Ggt1), suggesting that miR-
483 deficiency activates oxidation stress, which causes mitochondrial dysfunction and
simultaneously triggers an adaptive antioxidant stress response. Notably, miR-483 deletion
increases expression of a β-cell disallowed gene Aldh1a3, pointing to a direction linking
dysregulation of microRNAs with β-cell dedifferentiation. The objective of this project is to identity
new factors/pathways initiating beta-cell dedifferentiation. We hypothesize that miR-483
maintains β-cell identity by preventing beta-cell dedifferentiation, and miR-483 inactivation
induces alteration of antioxidant defense that in turn leads to mitochondrial dysfunction. We will
test this hypothesis with the following Aims: Aim 1. Determine the β-cell identity in miR-483
deficient mice after HFD feeding. Aim 2. Elucidate mechanism(s) by which miR-483 maintains β-
cell identity. Moreover, the therapeutic potential of miR-483 in preventing β-cell dedifferentiation
in human islets will be examined. The results obtained from this project will help understand the
underlying mechanisms of β-cell dedifferentiation and guide therapeutical treatments for diabetes.
This project will also provide research opportunities for both undergraduate and graduate
students.
摘要:
2型糖尿病是一种代谢紊乱,导致患者高血糖症。丧失功能性
β-细胞质量是从胰岛素抵抗发展到明显糖尿病的标志。新
有证据表明,由于β细胞去分化而导致的β细胞身份改变被认为是一种
糖尿病中β细胞丢失的新机制。然而,β细胞去分化的机制
仍有待调查。microRNAs(miRNAs)是一类小的非编码RNA,
通过抑制特定靶基因的表达来提高细胞功能和存活率。我们发现miR-
483在β细胞中高度表达,但在α细胞中表达较少。具有β细胞特异性缺失的小鼠
miR-483表现出饮食诱导的高血糖和葡萄糖耐量降低,而不改变
在β细胞团中。RNA-seq分析显示,miR-483失活导致细胞凋亡显著增加。
包括γ-谷氨酰转移酶(Ggt 1)在内的氧化应激标志物,表明miR-
483缺乏激活氧化应激,导致线粒体功能障碍,
同时触发了适应性抗氧化应激反应。值得注意的是,miR-483缺失
增加β细胞不允许的基因Aldh 1a 3的表达,指向一个方向,
微RNA的失调与β细胞去分化。本项目的目标是识别
启动β细胞去分化的新因子/途径。我们假设miR-483
通过防止β细胞去分化和miR-483失活来维持β细胞的特性
诱导抗氧化防御的改变,进而导致线粒体功能障碍。我们将
用以下目标来检验这个假设:目标1。确定miR-483中的β细胞身份
缺陷型小鼠后HFD喂养。目标2.阐明miR-483维持β-
细胞识别此外,miR-483在预防β细胞去分化中的治疗潜力是潜在的。
在人类胰岛中的作用。从这个项目中获得的结果将有助于了解
β细胞去分化的潜在机制,并指导糖尿病的治疗性治疗。
这个项目也将为本科生和研究生提供研究机会
学生
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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Xiaoqing Tang其他文献
Xiaoqing Tang的其他文献
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{{ truncateString('Xiaoqing Tang', 18)}}的其他基金
Role of miR-30d in insulin gene expression in pancreatic beta cells
miR-30d 在胰腺β细胞胰岛素基因表达中的作用
- 批准号:
8251702 - 财政年份:2009
- 资助金额:
$ 40.43万 - 项目类别:
Role of miR-30d in insulin gene expression in pancreatic beta cells
miR-30d 在胰腺β细胞胰岛素基因表达中的作用
- 批准号:
7708231 - 财政年份:2009
- 资助金额:
$ 40.43万 - 项目类别:
Role of miR-30d in insulin gene expression in pancreatic beta cells
miR-30d 在胰腺β细胞胰岛素基因表达中的作用
- 批准号:
7843608 - 财政年份:2009
- 资助金额:
$ 40.43万 - 项目类别:
Role of microRNAs in insulin production and secretion in pancreatic beta-cells
microRNA 在胰腺 β 细胞胰岛素产生和分泌中的作用
- 批准号:
7805283 - 财政年份:2007
- 资助金额:
$ 40.43万 - 项目类别:
Role of microRNAs in insulin production and secretion in pancreatic beta-cells
microRNA 在胰腺 β 细胞胰岛素产生和分泌中的作用
- 批准号:
7299166 - 财政年份:2007
- 资助金额:
$ 40.43万 - 项目类别:
Role of microRNAs in insulin production and secretion in pancreatic beta-cells
microRNA 在胰腺 β 细胞胰岛素产生和分泌中的作用
- 批准号:
7494462 - 财政年份:2007
- 资助金额:
$ 40.43万 - 项目类别:
Role of microRNAs in insulin production and secretion in pancreatic beta-cells
microRNA 在胰腺 β 细胞胰岛素产生和分泌中的作用
- 批准号:
7673563 - 财政年份:2007
- 资助金额:
$ 40.43万 - 项目类别:
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