Defining Molecular Determinants of Type 2 Diabetes Using Quantitative Proteomics
使用定量蛋白质组学定义 2 型糖尿病的分子决定因素
基本信息
- 批准号:8335569
- 负责人:
- 金额:$ 5.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:4 hydroxynonenalAffectAldehydesAll-Trans-RetinolAnalytical ChemistryAntioxidantsAttenuatedBTBR MouseBasic ScienceBindingBiochemicalBiochemistryBiogenesisBiologicalBiological AssayBiologyCell Culture TechniquesCell physiologyCellsCellular biologyCollectionControl AnimalDataData SetDevelopmentDiabetes MellitusDiseaseDoctor of PhilosophyElongation FactorEnvironmentEnzymesEpidemicEpitopesFamily memberFunctional disorderGeneticGoalsImmunoprecipitationIn VitroIncidenceInflammatoryInsulin ResistanceInvestigationLaboratoriesLinkLipid PeroxidationLiverLiver MitochondriaMass Spectrum AnalysisMetabolicMetabolic DiseasesMetabolismMinnesotaMitochondriaMitochondrial ProteinsModelingMolecularMonitorMusMutateNon-Insulin-Dependent Diabetes MellitusObesityOxidation-ReductionOxidoreductasePeripheralPhosphorylationPhosphorylation SitePlayPostdoctoral FellowPredispositionProductionProtein AnalysisProtein IsoformsProteinsProteomeProteomicsRNARNA InterferenceReactionRecombinant ProteinsRecombinantsResearchResearch Project GrantsResistanceRetinalRetinoidsRoleSelenocysteineSignal TransductionSite-Directed MutagenesisSurveysTestingTherapeutic InterventionTissuesTrainingTranslationsUnited StatesUniversitiesWisconsinWorkaldehyde dehydrogenasesbasecohortdiabeticgenetic regulatory proteinin vitro activityinsightinstrumentationmembermitochondrial dysfunctionmutantnoveloverexpressionoxidized lipidresearch studyresistant strainresponseselenoproteinstoichiometry
项目摘要
The objective of the proposed research is to determine how alterations in mitochondrial protein abundance and phosphorylation contribute to Type 2 Diabetes Mellitus (T2DM). Recent studies have linked mitochondrial dysfunction to insulin resistance. Dr. Alan Attie, co-sponsor of this proposal, uses genetics to understand the propensity to develop T2DM. Dr. David Pagliarini, sponsor of this proposal, focuses on the contribution of mitochondrial dysfunction to various diseases and understanding the basic science of mitochondrial biogenesis. Dr. Joshua Coon, the sponsor of my original application and a close collaborator on this proposal, is a leader in the development and application of mass spectrometry (MS) instrumentation for protein analysis. Having transition from the Coon group to start a second post-doc in the Pagliarini lab, I am continuing this project as the leading member of our interdisciplinary collaborative team.
I have completed collection of an exhaustive quantitative proteomics dataset that constituted the bulk of my proposed research for this project in my original application. I observed highly reproducible alterations in protein abundance and phosphorylation in liver mitochondria in a cohort of over forty mice, which are either susceptible (B6) or resistant (BTBR) to developing T2DM when made obese. I am currently using this proteomics screen as preliminary data for hypotheses-driven targeted biological investigation. The rationale for the proposed research is that determining how phosphorylation modulates redox-regulatory proteins in obesity will open new avenues for developing therapeutic interventions for type 2 diabetes. The co-sponsoring environment will help facilitate my goal of starting an independent academic laboratory focused on utilizing proteomics and targeted biology to study redox signaling in metabolic disease. I will employ both biochemical, cell biology, and targeted proteomic approaches to carrying out the following Aims:
Aim 1. Determine how the obesity-induced phosphorylation of the selenocysteine-specific elongation factor (Eefsec) regulates the production of redox-regulatory selenoproteins. I will test the hypothesis that enhanced obesity-induced phosphorylation of the non-mitochondrial isoform of Eefsec in diabetes- resistant B6 mice attenuates the production of inflammatory secreted selenoproteins without decreasing levels of key mitochondrial antioxidants, which are regulated by a mitochondrial-localized Eefsec isoform.
Aim 2. Elucidate the role of obesity-induced phosphorylation of mitochondrial redox enzymes in regulating the abundance of bioactive lipophilic aldehydes. I will test the hypothesis that obesity-induced phosphorylation of dehydrogenase/reductase SDR family member 4 (Dhrs4) alters the levels of retinoid metabolites in diabetic BTBR mice through regulating the enzyme's retinal reducing activity. A parallel hypothesis I will test is that induction of aldehyde dehydrogenase 3A2 (Aldh3a2) expression and phosphorylation is a compensatory response in obesity for detoxifying reactive lipid-peroxidation products.
这项研究的目的是确定线粒体蛋白丰度和磷酸化的改变如何导致2型糖尿病(T2 DM)。最近的研究将线粒体功能障碍与胰岛素抵抗联系起来。Alan Attie博士是该提案的共同发起人,他使用遗传学来了解发展T2 DM的倾向。大卫帕格里亚里尼博士,这一提案的发起人,重点是线粒体功能障碍对各种疾病的贡献,并了解线粒体生物发生的基础科学。约书亚库恩博士是我最初申请的发起人,也是这项提案的密切合作者,他是蛋白质分析质谱(MS)仪器开发和应用的领导者。从库恩小组过渡到帕利亚里尼实验室开始第二个博士后,我作为我们跨学科合作团队的领导成员继续这个项目。
我已经完成了详尽的定量蛋白质组学数据集的收集,这些数据集构成了我在原始申请中为该项目提出的大部分研究。我在一组超过40只小鼠中观察到肝脏线粒体中蛋白质丰度和磷酸化的高度可重复的变化,这些小鼠在肥胖时对发展T2 DM易感(B6)或耐药(BTBR)。我目前正在使用这个蛋白质组学筛选作为假设驱动的靶向生物学研究的初步数据。这项研究的基本原理是,确定磷酸化如何调节肥胖中的氧化还原调节蛋白,将为开发2型糖尿病的治疗干预开辟新途径。共同赞助的环境将有助于促进我的目标,即建立一个独立的学术实验室,专注于利用蛋白质组学和靶向生物学研究代谢疾病中的氧化还原信号。我将采用生物化学,细胞生物学和靶向蛋白质组学方法来实现以下目标:
目标1。确定肥胖诱导的硒代半胱氨酸特异性延伸因子(Eefsec)磷酸化如何调节氧化还原调节硒蛋白的产生。我将测试以下假设:在糖尿病抗性B6小鼠中Eefsec的非线粒体同种型的增强的肥胖诱导的磷酸化减弱炎性分泌的硒蛋白的产生,而不降低关键线粒体抗氧化剂的水平,其由脑内定位的Eefsec同种型调节。
目标二。阐明肥胖诱导的线粒体氧化还原酶磷酸化在调节生物活性亲脂性醛类丰度中的作用。我将测试的假设,即肥胖诱导的磷酸化脱氢酶/还原酶SDR家族成员4(Dhrs 4)改变类维生素A代谢物的水平,在糖尿病BTBR小鼠通过调节酶的视网膜还原活性。一个平行的假设,我将测试是醛脱氢酶3A 2(Aldh 3a 2)的表达和磷酸化的诱导是一种代偿反应,在肥胖解毒反应性脂质过氧化产物。
项目成果
期刊论文数量(0)
专著数量(0)
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Paul A. Grimsrud其他文献
Cysteine S-acetylation is a post-translational modification involved in metabolic regulation
半胱氨酸 S-乙酰化是参与代谢调节的翻译后修饰
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
E. K. Keenan;Akshay Bareja;Yannie Lam;Paul A. Grimsrud;M. Hirschey - 通讯作者:
M. Hirschey
Paul A. Grimsrud的其他文献
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{{ truncateString('Paul A. Grimsrud', 18)}}的其他基金
Novel roles of PDK4 in regulating mitochondrial protein phosphorylation, carbon flux and metabolic resilience
PDK4 在调节线粒体蛋白磷酸化、碳通量和代谢弹性中的新作用
- 批准号:
10604378 - 财政年份:2022
- 资助金额:
$ 5.57万 - 项目类别:
Novel roles of PDK4 in regulating mitochondrial protein phosphorylation, carbon flux and metabolic resilience
PDK4 在调节线粒体蛋白磷酸化、碳通量和代谢弹性中的新作用
- 批准号:
10444249 - 财政年份:2022
- 资助金额:
$ 5.57万 - 项目类别:
Defining Molecular Determinants of Type 2 Diabetes Using Quantitative Proteomics
使用定量蛋白质组学定义 2 型糖尿病的分子决定因素
- 批准号:
8255021 - 财政年份:2011
- 资助金额:
$ 5.57万 - 项目类别:
Defining Molecular Determinants of Type 2 Diabetes Using Quantitative Proteomics
使用定量蛋白质组学定义 2 型糖尿病的分子决定因素
- 批准号:
8517700 - 财政年份:2011
- 资助金额:
$ 5.57万 - 项目类别:
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