Post-Translational Regulation of Lipid Metabolism
脂质代谢的翻译后调控
基本信息
- 批准号:9889993
- 负责人:
- 金额:$ 38.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAntisense OligonucleotidesAtherosclerosisAttenuatedBlood CirculationCandidate Disease GeneCardiovascular DiseasesCardiovascular systemCause of DeathCell Surface ReceptorsCell surfaceCessation of lifeCholesterolCholesterol HomeostasisCytoplasmic TailDataDiabetes MellitusDiseaseDisease modelDyslipidemiasEndocytosisGene SilencingGenesGlucoseHealthHeart DiseasesHepaticHeritabilityHumanHuman GenomeHypertensionIn VitroKnockout MiceLDL Cholesterol LipoproteinsLipidsLiverLow Density Lipoprotein ReceptorLow-Density LipoproteinsMediatingMetabolicModelingMolecularMolecular TargetObesityPathway interactionsPlasmaPost-Translational RegulationProteomicsPublic HealthRecyclingRegulationRegulatory PathwayRisk FactorsSite-Directed MutagenesisStructureTestingTherapeuticTissuesTriglyceridesUbiquitinationUnited Statesbasecardiovascular disorder riskcardiovascular risk factorclinical careembryonic stem cellfeedinggenome wide association studyin vivoknockout animallipid metabolismloss of functionnoveloverexpressionprotein expressionreceptorreceptor expressionsmall moleculetherapeutic targettooltraituptakewestern diet
项目摘要
ABSTRACT
Elevated plasma cholesterol, triglycerides and metabolic complications such as obesity are among
the most important risk factors for cardiovascular disease (CVD). Understanding the factors and
mechanisms that regulate plasma low-density lipoprotein (LDL) cholesterol levels is of the utmost
importance. Increasing hepatic LDL receptor (LDLR) expression leads to increased uptake of LDL
cholesterol from the circulation, and has been a successful therapeutic strategy for treating CVD and
dyslipidemia. Here, we identify a novel gene that regulates hepatic LDLR and plasma LDL cholesterol
levels that is also a locus for LDL-C levels in human Genome-wide Association Studies. In extensive
preliminary data, we show that overexpression and silencing (using antisense oligonucleotides,
ASOs) of the candidate gene in vivo also alters plasma total and LDL cholesterol levels, and
reciprocally regulates the LDLR, suggesting the mechanism of action is directly through targeting the
LDLR. In Specific Aim 1 we will determine the molecular mechanism and structural requirements of
the regulation of LDLR protein expression and plasma LDL cholesterol levels. In Specific Aim 2, we
will use complimentary in vivo gain- and loss-of-function models, including tissue-specific knockout
mice and ASOs, to determine the therapeutic potential of specific ASO silencing agents in a relevant
disease model of atherosclerosis. In the current proposal we describe a novel post-translational
pathway that modulates plasma cholesterol homeostasis. Our findings identify a novel post-
translational regulation that can be targeted with ASO silencing agents and therefore has significant
therapeutic potential.
摘要
血浆胆固醇、甘油三酯升高和肥胖等代谢并发症都在其中
心血管疾病(CVD)最重要的危险因素。了解影响因素和
调节血浆低密度脂蛋白胆固醇水平的机制是最重要的
重要性。肝脏低密度脂蛋白受体(LDLR)表达增加导致低密度脂蛋白摄取增加
胆固醇从循环中释放,并已成为治疗心血管疾病和
血脂异常。在这里,我们发现了一个调节肝脏低密度脂蛋白受体和血浆低密度脂蛋白胆固醇的新基因。
在人类全基因组关联研究中,这也是低密度脂蛋白水平的一个位置。在广泛的
初步数据显示,过度表达和沉默(使用反义寡核苷酸,
体内候选基因的ASOS)也改变了血浆总胆固醇和低密度脂蛋白的水平,以及
相互调节LDLR,表明其作用机制是通过直接针对
LDLR。在具体目标1中,我们将确定分子机制和结构要求
低密度脂蛋白受体蛋白表达和血浆低密度脂蛋白水平的调节。在具体目标2中,我们
将使用免费的体内功能获得和丧失模型,包括组织特异性基因敲除
小鼠和ASO,以确定特定的ASO沉默药物在相关的治疗潜力
动脉粥样硬化的疾病模型。在目前的提案中,我们描述了一种新的后翻译
调节血浆胆固醇稳态的途径。我们的发现发现了一个新的帖子-
可被ASO沉默试剂靶向的翻译调控,因此具有重要意义
治疗潜力。
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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Elizabeth Joanna Tarling其他文献
Elizabeth Joanna Tarling的其他文献
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{{ truncateString('Elizabeth Joanna Tarling', 18)}}的其他基金
Targeting the gut-liver axis in cardiovascular disease
针对心血管疾病的肠肝轴
- 批准号:
10606375 - 财政年份:2022
- 资助金额:
$ 38.5万 - 项目类别:
ATP Binding Cassette Transporters in Health and Disease
健康和疾病中的 ATP 结合盒转运蛋白
- 批准号:
10390366 - 财政年份:2021
- 资助金额:
$ 38.5万 - 项目类别:
ATP Binding Cassette Transporters in Health and Disease
健康和疾病中的 ATP 结合盒转运蛋白
- 批准号:
10237095 - 财政年份:2021
- 资助金额:
$ 38.5万 - 项目类别:
ATP Binding Cassette Transporters in Health and Disease
健康和疾病中的 ATP 结合盒转运蛋白
- 批准号:
10552563 - 财政年份:2021
- 资助金额:
$ 38.5万 - 项目类别:
Role of ABCG1 in lipid homeostasis, inflammation and innate immunity
ABCG1 在脂质稳态、炎症和先天免疫中的作用
- 批准号:
8486177 - 财政年份:2013
- 资助金额:
$ 38.5万 - 项目类别:
Role of ABCG1 in lipid homeostasis, inflammation and innate immunity
ABCG1 在脂质稳态、炎症和先天免疫中的作用
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8724554 - 财政年份:2013
- 资助金额:
$ 38.5万 - 项目类别:
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