Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics
确定连接脂质信号传导和表观遗传学的亚细胞器
基本信息
- 批准号:9763211
- 负责人:
- 金额:$ 21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAcetyl Coenzyme AAcetylationAdverse eventAffectAnimalsApplications GrantsBiological ModelsCRISPR screenCandidate Disease GeneCaprylatesCarbonCatabolismCell CycleCell Cycle InhibitionCell LineCell NucleusCell ProliferationCell modelCell physiologyCellsChromatinCitratesCleaved cellCollaborationsCommunicationDataDepositionDietDietary InterventionDiseaseEndoplasmic ReticulumEnzymesEpigenetic ProcessEventFatty AcidsFutureGene ActivationGene ExpressionGene Expression ProfileGenerationsGenesGlucoseGlycolysisGoalsHealthHealth BenefitHistone AcetylationHistonesHumanIn VitroIncidenceIntelligenceKnock-outKnowledgeLeadLinkLipidsLocationLysineMalignant NeoplasmsMalignant neoplasm of liverMediatingMediator of activation proteinMedium chain triglyceridesMetabolicMetabolismMitochondriaMolecularMonitorNuclearNutrientOrganellesOutcomeOxidesPathway interactionsPharmacologyPlayPost-Translational Protein ProcessingPrevention therapyProductionProtein IsoformsProteinsPublic HealthPublishingRecurrenceReportingRepressionRoleSerumSignal TransductionSiteSourceStarvationSystemTestingTherapeuticTumor BurdenUniversitiesWood materialWorkbiological adaptation to stresscancer preventioncancer therapycdc Genesdetection of nutrientepidemiology studyepigenomegene inductiongenetic approachglucose metabolismhistone modificationimprovedinnovationlipid mediatorlipid metabolismmouse modelnovelnutrient metabolismoxidationoxidized lipidperoxisomepre-clinicalpreventprogramsresponsestable isotopetherapy designtreatment responsetreatment strategy
项目摘要
Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a
particular nutrient source. For example, glucose drives a gene expression program characterized
by activating genes involved in its metabolism, in part, by increasing glucose-derived histone
acetylation. We recently expanded the known metabolites that integrate into epigenetic signaling
and found that medium-chain lipid-derived acetyl-CoA is a major source of carbon for histone
acetylation. This signaling axis leads to activation of stress response genes, including lipid
metabolic genes, and inhibition of cell cycle gene expression. Our preliminary data presented in
this application expand upon these gene expression observations and reveal lipid oxidation
induces potent suppression of the cell cycle, lowers cellular proliferation across a range of cell
lines, and lowers tumor burden in a mouse model of liver cancer. However, a critical gap in our
knowledge remains that prevent us from fully understanding how the role of lipids and their
oxidation in cancer: In which sub-cellular organelle are medium-chain lipids oxidized to generate
acetyl-CoA for histone acetylation? Is the oxidation of MCTs required for their effect on cellular
proliferation? What are the key cellular mediators of these epigenetic signals? There is a critical
need to understand the full range of lipid’s molecular effects in order to enable more intelligent
therapies for cancer. Although it is widely accepted that mitochondria oxidize lipids and are prime
candidate sites of mediating communication between nutrients and the nucleus, no data exist to
support this notion. Therefore, the single objective of this exploratory grant application is to
determine the site(s) and molecular mediators of lipid signaling on epigenetics. Aim 1 will test
three candidate sites of lipid metabolism using a combination of pharmacological and genetic
approaches. In a complementary parallel approach, Aim 2 will perform an unbiased CRISPR-
Cas9 screen to identify genes that are required for the suppressive effects of medium-chain lipids
on cellular proliferation. This project is significant because it will explain the molecular
mechanisms by which lipids and their oxidation mediate the positive effects cellular proliferation
and cancer outcomes. We put forth conceptual and technical innovations that will both follow
directed hypotheses and allow unbiased discovery of the most important aspects of the response
to medium-chain lipids. Successful completion of this project will identify new aspects of inter-
organelle communication in cancer.
细胞整合营养感测和代谢,以协调适当的细胞反应,
特殊的营养来源。例如,葡萄糖驱动基因表达程序,其特征在于
通过激活参与其代谢的基因,部分通过增加葡萄糖衍生的组蛋白,
乙酰化我们最近扩大了已知的代谢物,整合到表观遗传信号
并发现中链脂质衍生的乙酰辅酶A是组蛋白的主要碳源
乙酰化这个信号轴导致应激反应基因的激活,包括脂质
代谢基因和抑制细胞周期基因表达。我们的初步数据显示,
本申请扩展了这些基因表达观察,并揭示了脂质氧化
诱导细胞周期的有效抑制,降低一系列细胞的细胞增殖,
线,并降低肝癌小鼠模型中的肿瘤负荷。然而,我们的一个关键差距是,
知识仍然阻止我们充分理解脂质及其
氧化:在癌症中,亚细胞器中的中链脂质被氧化,
乙酰辅酶A用于组蛋白乙酰化MCT的氧化是否是其对细胞的作用所必需的?
扩散?这些表观遗传信号的关键细胞介质是什么?存在一个临界
我们需要了解脂质分子的全部作用,以便能够更智能地
治疗癌症的方法尽管线粒体氧化脂质并在体内发挥重要作用已被广泛接受,
候选网站的调解之间的沟通营养物质和细胞核,没有数据存在,
支持这一观点。因此,本探索性赠款申请的唯一目标是
确定表观遗传学上脂质信号传导的位点和分子介质。目标1将测试
使用药理学和遗传学相结合的脂质代谢的三个候选位点
接近。在一种互补的并行方法中,Aim 2将执行无偏见的CRISPR-
Cas9筛选以鉴定中链脂质抑制作用所需的基因
对细胞增殖的影响。这个项目意义重大,因为它将解释
脂质及其氧化介导细胞增殖的积极作用的机制
和癌症的结果。我们提出了概念和技术创新,
有指导的假设,并允许无偏见的发现最重要的方面的反应
到中链脂质。成功完成这一项目将确定新的方面,
癌症中的细胞器通讯
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 }}
Matthew D Hirschey其他文献
Matthew D Hirschey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('Matthew D Hirschey', 18)}}的其他基金
Studies on the impact of acetyl-cysteine on metabolism
乙酰半胱氨酸对代谢影响的研究
- 批准号:
10574934 - 财政年份:2022
- 资助金额:
$ 21万 - 项目类别:
Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism
支链氨基酸代谢的翻译后和表观遗传控制
- 批准号:
10225807 - 财政年份:2018
- 资助金额:
$ 21万 - 项目类别:
Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism
支链氨基酸代谢的翻译后和表观遗传控制
- 批准号:
9930167 - 财政年份:2018
- 资助金额:
$ 21万 - 项目类别:
Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism
支链氨基酸代谢的翻译后和表观遗传控制
- 批准号:
10164761 - 财政年份:2018
- 资助金额:
$ 21万 - 项目类别:
Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease
新型 SIRT5 酶活性调节衰老和疾病的细胞机制
- 批准号:
8650231 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease
SIRT5调节衰老和疾病的机制研究
- 批准号:
10442722 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease
新型 SIRT5 酶活性调节衰老和疾病的细胞机制
- 批准号:
9210031 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease
新型 SIRT5 酶活性调节衰老和疾病的细胞机制
- 批准号:
8795651 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease
SIRT5调节衰老和疾病的机制研究
- 批准号:
10183107 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease
SIRT5调节衰老和疾病的机制研究
- 批准号:
10661571 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
相似海外基金
The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
- 批准号:
8783415 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
- 批准号:
8996048 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别:
The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
- 批准号:
9125794 - 财政年份:2014
- 资助金额:
$ 21万 - 项目类别: