Understanding the regulation of ER GPATs to control glycerolipid synthesis in disease
了解 ER GPAT 的调节以控制疾病中的甘油脂合成
基本信息
- 批准号:10230829
- 负责人:
- 金额:$ 6.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acyl Coenzyme AAcyltransferaseAddressAnimal ModelBindingBiochemistryBiologyCRISPR screenCRISPR/Cas technologyCaenorhabditis elegansCalcineurinCell physiologyCellsCellular MembraneCellular biologyCharacteristicsClustered Regularly Interspaced Short Palindromic RepeatsCoenzyme AComplexDevelopmentDiseaseDrosophila genusEF Hand MotifsEndoplasmic ReticulumEnzymesEquilibriumFatty AcidsFatty LiverFinancial compensationFutureGap JunctionsGenerationsGenesGeneticGenetic ScreeningGlycerolipid Metabolism PathwayHealthHeart failureHomeostasisHomologous ProteinHumanImpairmentInsulin ResistanceInvertebratesKnockout MiceLigaseLipidsLiverMammalian CellMediatingMembraneMetabolicMetabolic DiseasesMetabolismMolecularMutation AnalysisNonesterified Fatty AcidsOrganellesPPP3CB genePathologyPeroxisome Proliferator-Activated ReceptorsPhospholipidsPlayPost-Translational RegulationProcessProtein IsoformsProteinsProteomicsPublishingRegulationResearch PersonnelRoleSeriesSeveritiesTestingTimeTrainingTriglyceridesWorkalpha-glycerophosphoric acidbasecareercell behaviorcell typeexperimental studygenetic regulatory proteinhuman diseaseimprovedin vivoinnovationinsightlipid metabolismlipidomicslong chain fatty acidmouse modelnonalcoholic steatohepatitisnovelnovel therapeuticspost-doctoral trainingprotein acyltransferasetooltranscription factorwhole genome
项目摘要
PROJECT SUMMARY
Cells are dependent on fatty acids for the generation of membranes and the storage of energy. Within the cell,
fatty acids incorporate into membrane and storage glycerolipids through a series of metabolic enzymes. The
importance of this process to human health and disease is highlighted by the fact that many metabolic diseases
are characterized by dysfunctional lipid accumulation. Despite the importance of glycerolipid synthesis from fatty
acids cellular homeostasis and human disease, relatively little is known about the allosteric mechanisms that
regulate and control this process.
Using CRISPR genetic screens and unbiased lipidomics, the Birsoy lab recently identified calcineurin B
homologous protein 1 (CHP1) as a novel regulator of endoplasmic reticulum (ER) glycerolipid synthesis. In this
recently published study, our lab showed that loss off CHP1 severely blunted fatty acid incorporation and storage
in mammalian cells and invertebrate model organisms. Mechanistically, our lab demonstrated that CHP1 controls
glycerolipid synthesis by activating the ER GPAT, GPAT4, the initial rate limiting enzyme for glycerolipid
synthesis within the ER. The mechanism by which CHP1 activates GPAT4 is direct, as it was found that CHP1
and GPAT4 form a complex. This work identified CHP1 as one of few regulatory proteins of glycerolipid synthesis
described to date. We believe other such regulatory mechanisms control lipid metabolism likely exist.
This proposal seeks to more deeply understand the novel biology discovered in our preliminary work and
discover additional regulators of ER GPAT activity and function. In Aim 1, we seek to understand the precise
mechanism by which CHP1 binds and activates GPAT4. This will provide insight into the posttranslational
regulation of lipid metabolism and guide future study of other mechanisms analogous to CHP1. In Aim 2, we will
utilize a novel mouse model we recently generated to study ER GPAT function in vivo in both homeostasis and
disease such as NASH. In Aim 3, we seek to identify additional mechanisms regulating ER resident GPAT4
through unbiased genetic screening and proteomic approaches. Spanning basic biochemistry to mouse
modeling, this application will address outstanding fundamental questions in cellular metabolism and understand
this biology in the context of complex diseases afflicting humankind. The innovative studies proposed in this
application in addition to the personalized training plan, will provide rigorous postdoctoral training that will prepare
me to become an independent investigator.
项目总结
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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Timothy Cole Kenny其他文献
Timothy Cole Kenny的其他文献
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{{ truncateString('Timothy Cole Kenny', 18)}}的其他基金
Understanding the regulation of ER GPATs to control glycerolipid synthesis in disease
了解 ER GPAT 的调节以控制疾病中的甘油脂合成
- 批准号:
10671449 - 财政年份:2021
- 资助金额:
$ 6.56万 - 项目类别:
Understanding the regulation of ER GPATs to control glycerolipid synthesis in disease
了解 ER GPAT 的调节以控制疾病中的甘油脂合成
- 批准号:
10356065 - 财政年份:2021
- 资助金额:
$ 6.56万 - 项目类别:
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