The mTOR-ETV5 signaling in gastric X/A like cells and its role in hepatic lipid metabolism and steatosis
胃X/A样细胞中的mTOR-ETV5信号及其在肝脂质代谢和脂肪变性中的作用
基本信息
- 批准号:10414996
- 负责人:
- 金额:$ 60.03万
- 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:2021-07-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcylationAcyltransferaseAdultAffectAmericanBindingBiologicalBody Weight decreasedCellsCirrhosisDataDepositionDevelopmentEatingEventFRAP1 geneFatty LiverFood Intake RegulationGHS-R1aGene ExpressionGenesGoalsHealthHepaticHepatocyteHigh Fat DietHormonesHypothalamic structureKupffer CellsLipidsLiverMediatingModificationMusNamesNeuronsNutrientObesityOrganismPathogenesisPathway interactionsPrimary carcinoma of the liver cellsProductionRegulationRoleSignal PathwaySignal TransductionSiteSocietiesSteatohepatitisStomachTechniquesTestingTimeTransgenic MiceTransgenic OrganismsTriglyceridesVariantdes-n-octanoyl ghrelindesignenergy balanceghrelingrowth hormone secretagogue receptorinsightlipid metabolismnon-alcoholic fatty liver diseasenovelnovel therapeutic interventiontranscription factortreatment strategy
项目摘要
Our preliminary studies have identified a novel stomach-liver humoral axis. Mechanistic target of rapamycin (mTOR) signaling pathway in the gastric X/A like cells coordinates nutrient availability with the hepatic lipid metabolism via ghrelin. Our studies have also identified ETV5, an ETS-related transcriptional factor, as the novel downstream target of mTOR signaling. Further, ETV5 alters the expression of ghrelin O-acyltransferase and subsequent acylation of ghrelin. Although X/A like cells in the stomach produce and secrete both acyl- and desacyl-ghrelin, only acyl-ghrelin binds and activates its receptor: growth hormone secretagogue receptor 1a (GHSR1a). Acyl-ghrelin was originally demonstrated to act via the hypothalamus to stimulate food intake. Our data now indicate that acyl-ghrelin regulates hepatic lipid synthesis via its direct action on hepatocytes. We thus propose four aims to investigate the functions of gastric mTOR-ETV5 signaling pathway in the production and secretion of acyl-ghrelin and its effects on hepatic lipid metabolism. Aim 1 will establish ETV5 as the downstream target of mTOR, mediating its unique regulation of ghrelin acylation in X/A like cells. Aim 2, using transgenic mice in which mTOR signaling in gastric X/A like cells is either activated or suppressed, will demonstrate that gastric mTOR signaling affects hepatic lipid metabolism and the development of hepatic steatosis induced by a high-fat diet. Aim 3 will examine whether ETV5 in gastric X/A like cells alters hepatic lipid metabolism and the development of hepatic steatosis induced by a high-fat diet, using mice in which ETV5 gene expression in gastric X/A like cells is altered. Aim 4 will determine whether acyl-ghrelin mediates the effects of gastric mTOR on hepatic lipid metabolism via its activation of GHSR1a on hepatocytes, Kupffer cells and/or hypothalamic (HTH) neurons. We will use cell biological and transgenic techniques to achieve these goals. Completion of this proposal will advance a completely new therapeutic approach for NAFLD, one directed at gastric sites.
我们的初步研究已经确定了一种新型的胃-肝体液轴。在胃X/A样细胞中的雷帕霉素(mTOR)信号通路的机制靶标通过ghrelin协调营养利用与肝脏脂质代谢。我们的研究还确定了ETV 5,一种ETS相关的转录因子,作为mTOR信号转导的新下游靶点。此外,ETV 5改变生长素释放肽O-酰基转移酶的表达和随后的生长素释放肽酰化。虽然胃中的X/A样细胞产生并分泌酰基-和去酰基-ghrelin,但只有酰基-ghrelin结合并激活其受体:生长激素促分泌素受体1a(GHSR 1a)。酰基饥饿素最初被证明通过下丘脑刺激食物摄入。我们的数据表明,酰基-生长激素释放肽通过其对肝细胞的直接作用来调节肝脏脂质合成。因此,我们提出了四个目的,以研究胃mTOR-ETV 5信号通路在酰基-ghrelin的产生和分泌中的功能及其对肝脏脂质代谢的影响。目的1将ETV 5作为mTOR的下游靶点,介导其在X/A样细胞中对ghrelin酰化的独特调节。目的2,使用胃X/A样细胞中mTOR信号被激活或抑制的转基因小鼠,将证明胃mTOR信号影响肝脏脂质代谢和高脂饮食诱导的肝脂肪变性的发展。目的3将使用胃X/A样细胞中ETV 5基因表达改变的小鼠来检查胃X/A样细胞中ETV 5是否改变肝脏脂质代谢和由高脂饮食诱导的肝脂肪变性的发展。目的4将确定酰基-ghrelin是否通过其激活肝细胞、枯否细胞和/或下丘脑(HTH)神经元上的GHSR 1a来介导胃mTOR对肝脏脂质代谢的影响。我们将使用细胞生物学和转基因技术来实现这些目标。该提案的完成将推进NAFLD的全新治疗方法,一种针对胃部位的治疗方法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Weizhen Zhang其他文献
Weizhen Zhang的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Weizhen Zhang', 18)}}的其他基金
The mTOR-ETV5 signaling in gastric X/A like cells and its role in hepatic lipid metabolism and steatosis
胃X/A样细胞中的mTOR-ETV5信号及其在肝脂质代谢和脂肪变性中的作用
- 批准号:
10581641 - 财政年份:2021
- 资助金额:
$ 60.03万 - 项目类别:
The mTOR-ETV5 signaling in gastric X/A like cells and its role in hepatic lipid metabolism and steatosis
胃X/A样细胞中的mTOR-ETV5信号及其在肝脂质代谢和脂肪变性中的作用
- 批准号:
10274428 - 财政年份:2021
- 资助金额:
$ 60.03万 - 项目类别:
相似海外基金
Design of chemical probes for hedgehog acyltransferase
Hedgehog酰基转移酶化学探针的设计
- 批准号:
2600595 - 财政年份:2022
- 资助金额:
$ 60.03万 - 项目类别:
Studentship
Identification of the glycolytic enzyme palmitoyl acyltransferase
糖酵解酶棕榈酰酰基转移酶的鉴定
- 批准号:
571756-2022 - 财政年份:2022
- 资助金额:
$ 60.03万 - 项目类别:
University Undergraduate Student Research Awards
The role of LYCAT acyltransferase in phagocytosis and immune function
LYCAT酰基转移酶在吞噬作用和免疫功能中的作用
- 批准号:
564899-2021 - 财政年份:2021
- 资助金额:
$ 60.03万 - 项目类别:
University Undergraduate Student Research Awards
Targeting a Human Acyltransferase for Broad-Spectrum Antivirals
靶向人类酰基转移酶的广谱抗病毒药物
- 批准号:
10223496 - 财政年份:2021
- 资助金额:
$ 60.03万 - 项目类别:
Hedgehog acyltransferase : structure and function in health and disease
Hedgehog酰基转移酶:健康和疾病中的结构和功能
- 批准号:
BB/T01508X/1 - 财政年份:2020
- 资助金额:
$ 60.03万 - 项目类别:
Research Grant
Is transcription factor TEAD a missing protein lysine fatty acyltransferase?
转录因子 TEAD 是缺失的蛋白质赖氨酸脂肪酰基转移酶吗?
- 批准号:
19K22271 - 财政年份:2019
- 资助金额:
$ 60.03万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Protein acyltransferase mediated S-palmitoylation and its Importance in Innate Immunity and Lipid Metabolism.
蛋白质酰基转移酶介导的 S-棕榈酰化及其在先天免疫和脂质代谢中的重要性。
- 批准号:
401169 - 财政年份:2019
- 资助金额:
$ 60.03万 - 项目类别:
Operating Grants
Basic research on the development of therapeutic agents for Alzheimer's disease using Acyl-CoA:cholesterol acyltransferase inhibitor
利用酰基辅酶A:胆固醇酰基转移酶抑制剂开发阿尔茨海默病治疗剂的基础研究
- 批准号:
19K07093 - 财政年份:2019
- 资助金额:
$ 60.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Defining the Molecular Architecture for Transmembrane Acylation by a Membrane Bound O-Acyltransferase
定义膜结合 O-酰基转移酶跨膜酰化的分子结构
- 批准号:
10246913 - 财政年份:2019
- 资助金额:
$ 60.03万 - 项目类别:
Characterization of Xenopus laevis DHAP acyltransferase
非洲爪蟾 DHAP 酰基转移酶的表征
- 批准号:
540689-2019 - 财政年份:2019
- 资助金额:
$ 60.03万 - 项目类别:
University Undergraduate Student Research Awards