The Role of KBTBD2 in Lipodystrophy, Insulin Resistance, and Diabetes
KBTBD2 在脂肪营养不良、胰岛素抵抗和糖尿病中的作用
基本信息
- 批准号:10468738
- 负责人:
- 金额:$ 24.9万
- 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:2020-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdipocytesAdipose tissueAffectAntibodiesBTB/POZ DomainBindingBiochemicalBiochemistryBiologicalBiological AssayBlood GlucoseBody fatCellsClustered Regularly Interspaced Short Palindromic RepeatsComplexCre-LoxPDataDefectDevelopmentDiabetes MellitusDiabetic mouseExhibitsFastingFatty LiverFatty acid glycerol estersGenesGeneticGenetic ScreeningGenetic TranscriptionGlucoseGrowthHomeostasisHumanIn VitroInsulin ResistanceInsulin Signaling PathwayKnock-outLipidsLipodystrophyLiverMaintenanceMalignant NeoplasmsMass Spectrum AnalysisMediatingMedical centerMentorsMetabolicMetabolic DiseasesModificationMonoubiquitinationMusMuscleMutant Strains MiceMutateNon-Insulin-Dependent Diabetes MellitusNonsense MutationObesityPathway interactionsPhasePhenotypePhosphorylationPhosphotransferasesPhysiologic MonitoringPlayPolyubiquitinationPost-Translational Protein ProcessingPost-Translational RegulationPrevalenceProteinsPublic HealthRegulationResearchResearch PersonnelRoleSiteSystemTestingTetanus Helper PeptideTherapeuticTimeTissuesTrainingTransplantationUbiquitinationUndifferentiatedWorkadipocyte differentiationcausal variantconditional knockoutcullin-3diabetes pathogenesisdiabetes riskdiet-induced obesityfasting glucoseglobal healthimprovedin vivoinhibitorinsightinsulin sensitivityinsulin signalingmetabolic phenotypemouse geneticsmouse modelnew therapeutic targetnovelnull mutationoverexpressionprotein functionrecruittoolubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Adipose tissue is critical for whole body energy homeostasis. Both obesity and lipodystrophy (caused by
loss of fat) are associated with diabetes and insulin resistance. Our recent work identified a new mutant mouse,
termed teeny, that exhibited growth retardation, lipodystrophy, extreme insulin resistance, severe diabetes with
fasting glucose as high as 600-700 mg/dL, and fatty liver. The teeny phenotype is caused by a null mutation in
the Kelch repeat and BTB (POZ) Domain containing 2 (KBTBD2), which has no previously assigned functions.
We found that KBTBD2 operates as an E3 ubiquitin ligase to regulate the insulin signaling pathway by targeting
the degradation of the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85α. This proposal will further
explore the role of KBTBD2 in lipodystrophy, insulin resistance, and diabetes, and will seek to identify
mechanistically related regulators of diabetes and obesity. In the mentored K99 phase, mice will be generated
to manipulate Kbtbd2 expression in different tissues to study its tissue-specific functions, and to dissect the role
of each tissue in the development of teeny phenotype (Aim 1). I found that KBTBD2 harbors a YXXM motif,
which may be phosphorylated in order to recruit p85α. The phosphorylation of KBTBD2 could explain why p85α
is selectively degraded in different cells and tissues. This, in turn, would suggest that KBTDB2 itself might be
subject to post-translational regulation depending upon tissue, developmental stage, and/or metabolic status.
The focus of Aim 2 will be to study the post-translational modification of KBTBD2. In the independent R00 phase,
I will further explore the biological consequences of the observed p85α mono-ubiquitination (Aim 3). The
transcriptional suppression of Kbtbd2 in diet-induced obesity, leading to the accumulation of p85α, prompts us
to search for deubiquitinases, which might be targeted by inhibitors to reduce the risk of diabetes in obesity. In
preliminary studies, several candidate p85α deubiquitinases have been identified. To identify new genes that
are involved in obesity and diabetes, we have established several forward genetic screens in mice and found
interesting hits. Among these, a second BTB protein (RHOBTB2) may act within the overall framework we have
built. In Aim 4, I will study the mechanism of deubiquitinases and other newly identified regulators in obesity and
diabetes. Successful completion of the aims outlined in this proposal will improve our understanding of KBTBD2
and may provide new targets for diabetes treatment. To accomplish the proposed research, I will include Dr.
Philipp Scherer (UT Southwestern Medical Center) as my co-mentor during the mentored K99 phase to gain
more training in adipocyte and diabetes research. My mentor, Dr. Bruce Beutler, has established a unique
forward genetic initiative with the ability to identify causative mutations in real time. I will continue working on
newly identified regulators of obesity and diabetes from the established forward genetic screens in the
independent R00 phase. This training will allow me to expand my expertise and help my transition into a
successful independent academic researcher.
项目总结
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Generation of epitope tag knock-in mice with CRISPR-Cas9 to study the function of endogenous proteins.
- DOI:10.1016/j.xpro.2023.102518
- 发表时间:2023-09-15
- 期刊:
- 影响因子:0
- 作者:Zhang, Zhao
- 通讯作者:Zhang, Zhao
Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2.
Hilnc 的缺失通过结合 IGF2BP2 预防饮食诱导的肝脂肪变性
- DOI:10.1038/s42255-021-00488-3
- 发表时间:2021-11
- 期刊:
- 影响因子:20.8
- 作者:Jiang, Yiao;Peng, Jiayin;Song, Jiawen;He, Juan;Jiang, Man;Wang, Jia;Ma, Liya;Wang, Yuang;Lin, Moubin;Wu, Hailong;Zhang, Zhao;Gao, Dong;Zhao, Yun
- 通讯作者:Zhao, Yun
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Zhao Zhang其他文献
Zhao Zhang的其他文献
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{{ truncateString('Zhao Zhang', 18)}}的其他基金
The Role of Gm4951 in Nonalcoholic Fatty Liver Disease
Gm4951 在非酒精性脂肪肝中的作用
- 批准号:
10544345 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
The Role of Gm4951 in Nonalcoholic Fatty Liver Disease
Gm4951 在非酒精性脂肪肝中的作用
- 批准号:
10339213 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Regulation, function, and impact of developmental retrotransposon activation
发育逆转录转座子激活的调节、功能和影响
- 批准号:
10177576 - 财政年份:2021
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$ 24.9万 - 项目类别:
Regulation, function, and impact of developmental retrotransposon activation
发育逆转录转座子激活的调节、功能和影响
- 批准号:
10549855 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
Regulation, function, and impact of developmental retrotransposon activation
发育逆转录转座子激活的调节、功能和影响
- 批准号:
10373055 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
Quantitative characterization of neuronal trans-SNARE complexes using DNA origami
使用 DNA 折纸对神经元 trans-SNARE 复合物进行定量表征
- 批准号:
10281683 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
The Role of KBTBD2 in Lipodystrophy, Insulin Resistance, and Diabetes
KBTBD2 在脂肪营养不良、胰岛素抵抗和糖尿病中的作用
- 批准号:
10213315 - 财政年份:2020
- 资助金额:
$ 24.9万 - 项目类别:
Somatic transposition-mediated genome variegation during development, disease and aging conditions
发育、疾病和衰老条件下体细胞转座介导的基因组变异
- 批准号:
9001476 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
Somatic transposition-mediated genome variegation during development, disease and aging conditions
发育、疾病和衰老条件下体细胞转座介导的基因组变异
- 批准号:
10043992 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
Somatic transposition-mediated genome variegation during development, disease and aging conditions
发育、疾病和衰老条件下体细胞转座介导的基因组变异
- 批准号:
9349391 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
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