Role of Atp6ap2 in renal proximal tubule lipotoxicity
Atp6ap2 在肾近曲小管脂毒性中的作用
基本信息
- 批准号:10591837
- 负责人:
- 金额:$ 16.67万
- 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:2023-02-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AlbuminsAnimalsAreaAwardBasic ScienceBindingBiomedical ResearchCell DeathCellsChronic Kidney FailureComplementComplexCoupledDataDevelopmentDevelopment PlansDiabetes MellitusEndocrinologyEndocytosisEnvironmentEpithelial CellsExcretory functionFRAP1 geneFatty AcidsFiltrationFoundationsFunctional disorderFutureGenus HippocampusGoalsHigh Fat DietHigh Pressure Liquid ChromatographyIn VitroInjury to KidneyIntracellular Accumulation of LipidsInvestigationKidneyKidney DiseasesKnock-outKnockout MiceLDL-Receptor Related Protein 2LaboratoriesLipidsMagnetic Resonance ImagingMass Spectrum AnalysisMediatingMentorsMentorshipMethodsMicroscopyModificationMusNephronsObesityObesity EpidemicObesity associated kidney diseaseOxidative StressPathologyPeripheralPhysiciansPredispositionPrevalencePreventionPrevention strategyProcessProton-Translocating ATPasesProximal Kidney TubulesResearchResearch TrainingRisk FactorsRoleScanningScienceScientistSignal TransductionSmall Interfering RNATechniquesTestingTimeTissuesTrainingTransgenic MiceTranslational ResearchUniversitiesVirginiaWritingabsorptioncareercareer developmentcell typediabeticdiet-induced obesityendoplasmic reticulum stressexperiencefatty acid oxidationin vitro Modelin vivointerestintravital imagingintrinsic factor-cobalamin receptorkidney cellkidney cortexkidney dysfunctionknock-downlipid metabolismlipidomicsmicroscopic imagingmitochondrial dysfunctionmouse modelnew therapeutic targetnovel strategiesnovel therapeutic interventionobesity managementobesity treatmentoxidationpharmacologicpreventreceptor mediated endocytosisresearch facilityuptakeurinaryvacuolar H+-ATPase
项目摘要
Project Summary
The rising rates of obesity worldwide contribute directly to an increased prevalence of chronic kidney
disease. With current methods for mitigating obesity related kidney injury incompletely effective, novel
approaches to this problem are needed. In renal lipotoxicity, toxic lipid metabolites accumulate in certain
kidney cell types, including proximal tubule cells. This has recently been identified as an important mechanism
behind obesity related kidney disease but is also not well understood.
In obesity, greater proximal tubule uptake of lipid occurs through increased luminal endocytosis of fatty
acid bound to albumin, facilitated by interaction of the vacuolar H+ -ATPase and mTOR with the
megalin/cubulin complex. At the same time, decreased activation of renal AMPK in obesity leads to decreased
fatty acid oxidation through inactivation of PGC-1α, and CPT1A, further resulting in intracellular lipid
accumulation in the proximal tubule. ATP6AP2 is an integral component of the vacuolar H+ -ATPase and has
also been shown to have a role in intracellular energy signaling including inhibition of AMPK and PGC-1α as
well as activation of mTOR in diabetes. Renal cortical ATP6AP2 expression increases in obesity but its role in
lipotoxicity is unknown. Mice with nephron specific ATP6AP2 knockout during obesity have increased urinary
excretion of albumin and fatty acid, reduced proximal tubule lipid content during diet induced obesity,
decreased endoplasmic reticulum stress, a marker of lipotoxicity, and altered intrarenal lipid profile. This
proposal will test the hypothesis that in obesity ATP6AP2 promotes proximal tubule lipotoxicity through
endocytosis of albumin bound fatty acid as well as reduced intracellular fatty acid oxidation. Aim 1 proposes
that ATP6AP2 increases fatty acid endocytosis through the H+ -ATPase/mTOR/megalin/cubulin. Aim 2 will
test the hypothesis that ATP6AP2 reduces fatty acid oxidation through AMPK/PGC-1α/CPT1A..
This project will also greatly facilitate my career development toward the goal of becoming a fully
independent physician scientist performing basic and translational research. The career development plan
described in this application will include formal training in lipid science and lipidomics, the use of transgenic
mouse models, microscopy, and scientific writing, as well as mentorship by leaders in endocrinology and lipid
science including my mentors Drs. Helmy Siragy and Thurl Harris. This will take place at the University of
Virginia, an excellent research training environment with state-of-the art research facilities and core
laboratories as well as a superb academic environment for early career scientists. Data generated by the
proposed studies will establish the basis for an independent research career, distinct from my mentors.
项目摘要
全球肥胖率的上升直接导致慢性肾脏病的患病率增加。
疾病由于目前减轻肥胖相关肾损伤的方法不完全有效,
需要解决这个问题的方法。在肾脂毒性中,毒性脂质代谢产物在某些细胞中积累,
肾细胞类型,包括近端小管细胞。这一点最近被确定为一个重要机制,
与肥胖相关的肾脏疾病的背后,但也没有得到很好的理解。
在肥胖症中,近曲小管对脂质的摄取增加是通过增加管腔内的脂肪内吞作用而发生的。
通过空泡H+ -ATP酶和mTOR与白蛋白的相互作用,
megalin/cubulin复合物。与此同时,肥胖患者肾脏AMPK的活化减少,
通过PGC-1α和CPT 1A失活的脂肪酸氧化,进一步导致细胞内脂质
在近端小管中积聚。ATP 6AP 2是液泡H+ -ATP酶的组成部分,
还显示在细胞内能量信号传导中起作用,包括抑制AMPK和PGC-1α,
以及糖尿病中mTOR的激活。肥胖患者肾皮质ATP 6AP 2表达增加,但其在肥胖中的作用
脂毒性未知。肥胖期间肾单位特异性ATP 6AP 2敲除小鼠的尿
白蛋白和脂肪酸的排泄,在饮食诱导的肥胖期间近端小管脂质含量的降低,
降低内质网应激,脂毒性的标志物,改变肾内脂质谱。这
该提案将检验肥胖症中ATP 6AP 2通过以下途径促进近端小管脂毒性的假设:
白蛋白结合脂肪酸的内吞作用以及减少的细胞内脂肪酸氧化。目标1建议
ATP 6AP 2通过H+ -ATP酶/mTOR/megalin/cubulin增加脂肪酸内吞作用。目标2将
检验ATP 6AP 2通过AMPK/PGC-1α/CPT 1A减少脂肪酸氧化的假设。
这个项目也将极大地促进我的职业发展,朝着成为一个全面的
从事基础和转化研究的独立医生科学家。职业发展计划
本申请中描述的方法将包括脂质科学和脂质组学的正式培训,转基因药物的使用,
小鼠模型,显微镜和科学写作,以及内分泌学和脂质领导人的指导
包括我的导师Helmy Siragy博士和Thur Harris博士。这将发生在大学的
弗吉尼亚州,一个优秀的研究培训环境与国家的最先进的研究设施和核心
实验室以及一流的学术环境,为早期的职业科学家。生成的数据
建议的研究将为独立的研究生涯奠定基础,与我的导师不同。
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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Silas A Culver其他文献
Dopamine-Secreting Carotid Body Paraganglioma in a Patient With SDHB Mutation
SDHB 突变患者的多巴胺分泌性颈动脉体副神经节瘤
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Katherine Mustafa;Sara Zadeh;Silas A Culver - 通讯作者:
Silas A Culver
Silas A Culver的其他文献
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{{ truncateString('Silas A Culver', 18)}}的其他基金
PRR Promotes Obesity Related Hypertension via alpha-ENaC
PRR 通过 alpha-ENaC 促进肥胖相关高血压
- 批准号:
9327492 - 财政年份:2017
- 资助金额:
$ 16.67万 - 项目类别:
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