Investigating Ptpn18 as a regulator of diet induced obesity, cell proliferation, and insulin resistance
研究 Ptpn18 作为饮食引起的肥胖、细胞增殖和胰岛素抵抗的调节剂
基本信息
- 批准号:9905938
- 负责人:
- 金额:$ 2.46万
- 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:2020-03-01 至 2020-07-17
- 项目状态:已结题
- 来源:
- 关键词:AdipocytesAdipose tissueAffectAmino Acid SubstitutionAreaBiological ModelsBody TemperatureBody WeightBody fatCRISPR/Cas technologyCell Culture TechniquesCell ProliferationCellsCollaborationsConsumptionDataData AnalysesDatabasesDiabetes MellitusDietDiseaseDyslipidemiasEatingEducational process of instructingEnergy MetabolismEnvironmentEpidemicEpidermal Growth Factor ReceptorEpithelialFatty LiverFatty acid glycerol estersFlow CytometryFundingGenesGeneticGenetic ScreeningGrowth FactorGrowth Factor ReceptorsHarvestHeritabilityHeterogeneityHigh Fat DietHumanHuman GeneticsImmunoprecipitationInbred Strains MiceInfiltrationInflammationInflammatoryInsulin ResistanceKnock-in MouseLaboratoriesLeptinLeptin deficiencyLinkMalnutritionMass Spectrum AnalysisMeasuresMelanocortin 4 ReceptorMetabolicMetabolic DiseasesMethodsMusNon-Insulin-Dependent Diabetes MellitusObesityObesity EpidemicOvernutritionPathway interactionsPeptidesPhilosophyPhosphoric Monoester HydrolasesPhosphorylationPhysiologicalPhysiologyPostdoctoral FellowProtein Tyrosine PhosphataseProteinsRegulationResearchResearch PersonnelResistanceRoleSecureSignal PathwaySignal TransductionStainsSucroseSystemTechniquesTelemetryTestingTimeTrainingTyrosineWeight GainWild Type Mousecell typeexperimental studygene discoveryloss of functionmacrophagemalignant breast neoplasmmetabolic phenotypemouse modelmutantnew therapeutic targetnovelobesity geneticsobesity treatmentobesogenicoverexpressionrecruitrepositoryresponseskillstherapeutic target
项目摘要
Project Summary/Abstract
The world has crossed a threshold where people suffering from diseases of overnutrition now outnumber
those who suffer from undernutrition. The world obesity epidemic has resulted in an unprecedented diabetes
epidemic. In a genetic screen, our laboratory recently identified a gene (Ptpn18) that affects the increase in
body fat that results from consumption of a Western (high-fat/high-sucrose) diet. Prior to our studies, a
physiological role for PTPN18 in diet-induced obesity had not been described. However, in breast cancer,
PTPN18 regulates epithelial growth factor (EGF) signaling by dephosphorylating and repressing human EGF
receptor 2 (HER2). Through CRSPR/Cas9 gene editing, our lab derived a knock-in mouse with a single amino
acid substitution in Ptpn18; D197A, which abolishes its phosphatase activity. The knock-in mice have a
dramatic resistance to diet-induced obesity. Therefore, I hypothesize that Ptpn18 is a critical regulator of
weight gain and cell proliferation within adipose tissue. I propose to: 1) Identify the direct physiological
substrates of Ptpn18 in adipose tissue, 2) Evaluate the role of PTPN18 in cell proliferation within adipose
tissue and adipose tissue inflammation, and 3) Characterize energy expenditure and food intake in Ptpn18D197A
mice. The results of the proposed experiments will significantly advance our understanding of the function of
Ptpn18 and its link to diet-induced obesity. Through the discovery of direct substrates of Ptpn18, I expect to
find a novel pathway for regulation of adipose tissue function and its response to diet. While Ptpn18 is unlikely
to be a direct therapeutic target, it is possible that the pathway I discover can be mined for therapeutic targets.
The overall theme of research in the Attie lab is the genetics of obesity and type 2 diabetes. Our laboratory
uses mouse genetics to identify gene loci that contribute to obesity, type 2 diabetes, and metabolic disorders
related to obesity and diabetes; e.g. hepatic steatosis and dyslipidemia. During the time in which I am a
postdoctoral fellow, I will be trained in new experimental methods, including mass spectrometry, flow
cytometry, and large-scale data analysis. I will also gain new expertise in mouse physiology, while refining
those skills and techniques I already possess. Dr. Attie will also guide me in developing a teaching philosophy
statement and teaching portfolio, as well as providing guidance in securing independent funding. UW-Madison
has an outstanding training environment, dedicated to and supportive of collaborative efforts. I will have the
support and training necessary to develop as an independent researcher.
项目总结/摘要
世界已经跨越了一个门槛,营养过剩疾病的患者现在超过了
那些营养不良的人。世界肥胖流行导致了前所未有的糖尿病
疫情在遗传筛查中,我们的实验室最近发现了一个基因(Ptpn 18),它会影响
因食用西方(高脂肪/高蔗糖)饮食而产生的体脂。在我们的研究之前,
PTPN 18在饮食诱导的肥胖症中的生理作用尚未被描述。然而,在乳腺癌中,
PTPN 18通过去磷酸化和抑制人EGF调节EGF信号传导
受体2(HER 2)。通过CRSPR/Cas9基因编辑,我们的实验室获得了一个具有单个氨基酸的敲入小鼠,
在Ptpn 18; D197 A中的酸取代,这消除了其磷酸酶活性。基因敲入的小鼠
对饮食引起的肥胖有显著的抵抗力。因此,我假设Ptpn 18是一个关键的调节因子,
体重增加和脂肪组织内的细胞增殖。我建议:1)确定直接的生理
2)评估PTPN 18在脂肪组织内细胞增殖中的作用,
组织和脂肪组织炎症,以及3)表征Ptpn 18 D197 A中的能量消耗和食物摄入
小鼠这些实验的结果将大大促进我们对
ptpn 18及其与饮食诱导肥胖的关系。通过发现Ptpn 18的直接底物,我希望
为调节脂肪组织功能及其对饮食的反应找到了新的途径。虽然Ptpn 18不太可能
作为一个直接的治疗靶点,我发现的途径有可能被挖掘为治疗靶点。
Attie实验室研究的总体主题是肥胖和2型糖尿病的遗传学。本实验室
使用小鼠遗传学来确定导致肥胖、2型糖尿病和代谢紊乱的基因位点
与肥胖和糖尿病相关;例如肝脂肪变性和血脂异常。在我作为一个
博士后研究员,我将在新的实验方法,包括质谱,流
流式细胞术和大规模数据分析。我还将获得老鼠生理学方面的新专业知识,
我已经掌握的技能和技巧阿蒂博士还将指导我发展一种教学理念
报告和教学组合,并提供指导,以确保独立的资金。UW-Madison
拥有出色的培训环境,致力于并支持合作努力。我将有
作为独立研究人员发展所需的支持和培训。
项目成果
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