Impact of fasting on intestinal stem cells and cancer
禁食对肠道干细胞和癌症的影响
基本信息
- 批准号:10653895
- 负责人:
- 金额:$ 37.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-hydroxy-3-methylglutaryl-coenzyme AAPC geneAcetyl Coenzyme AAffectAgonistCellsCoenzyme AColonColon CarcinomaDietEngineeringEnzymesFastingHDAC1 geneHealthHealth PromotionHistone Deacetylase InhibitorHumanInjuryIntestinal CancerIntestinal NeoplasmsIntestinesKetone BodiesKetonesLGR5 geneLigaseLongevityMalignant NeoplasmsMammalsMediatingMetabolicMetabolismMitochondriaModelingMusNatural regenerationNonesterified Fatty AcidsOrganoidsPPAR deltaPathway interactionsPhysiologicalPopulationProcessProductionRegimenRoleSecretory CellSignal TransductionSmall IntestinesSourceTestingTherapeuticTissuesWhole OrganismWorkadult stem cellbeta-Hydroxybutyratebiosynthetic productfatty acid oxidationgene repressionimprovedin vivoinsightintestinal tumorigenesisketogenticmouse modelnovelnovel therapeuticsoxidationpreventprogramsrepairedresponsestem cell agingstem cell functionstem cellsstemnesstissue repairtransplant modeltumortumor growthtumor initiationtumor progressiontumorigenesis
项目摘要
PROJECT SUMMARY
Fasting regimens can increase lifespan, improve health or both in diverse species including mammals. Fasting
also has an emerging role in inhibiting tumor growth, yet little is known about how it impacts tumor initiation or
how fasting-imposed metabolism can be therapeutically exploited to treat established tumors. Given that adult
stem cells coordinate tissue adaptation and drive tumorigenesis, understanding the mechanism(s) that mediate
their response to fasting has important implications for enhancing tissue repair after injury or aging where stem
cell function declines, and may provide new therapeutic inroads for cancer. In the mouse intestine, where
LGR5+ intestinal stem cells (ISCs) drive the rapid renewal of the intestinal lining, we showed that fasting
augments ISC function by inducing a peroxisome proliferator-activated receptor delta (PPARd) driven fatty acid
oxidation (FAO) program, which breaks down free fatty acids into acetyl-CoA units. This work raises the critical
question of how fasting functions through the FAO pathway to regulate intestinal stemness. We hypothesize
that beta-hydroxybutyrate (βOHB), a ketone body and biosynthetic product of FAO generated acetyl-
CoA, functions as a signaling metabolite and energetic substrate that mediates the ISC fasting
response. In support of this idea, we recently found that the LGR5+ ISCs strongly express enzymes of the
ketogenic pathway that produce βOHB, including its rate-limiting enzyme HMGCS2 (3-hydroxy-3-
methylglutaryl-CoA synthetase 2), compared to non-stem cell populations and that fasting strongly elevates
HMGCS2 and βOHB levels in ISCs. HMGCS2 loss in the small intestine reduces βOHB levels in LGR5+ ISCs
and skews their differentiation towards secretory cell fates, which we showed can be rescued by exogenous
βOHB and class I histone deacetylases (HDACs) inhibitor treatment. Mechanistically, βOHB acts as a
signaling metabolite to reinforce the NOTCH program in ISCs by inhibiting HDAC-mediated transcriptional
repression. Dynamic control of βOHB levels in ISCs, therefore, could enable the rapid adaptation of the
intestine to diverse physiological states like fasting. Many important questions that form the basis of our aims
remain regarding the role ketone bodies as effectors of the fasting response in ISCs such as understanding the
in vivo signaling (Aim 1) and energetic (Aim 2) roles of βOHB in this process. Another critical question is to
decipher how the fasting-induced FAO program in ISCs influences tumor initiation and progression (Aim 3).
!
项目摘要
禁食方案可以延长寿命,改善健康或在包括哺乳动物在内的不同物种中两者兼而有之。空腹
在抑制肿瘤生长方面也有新的作用,但关于它如何影响肿瘤的发生或
如何在治疗上利用禁食强加的代谢来治疗已建立的肿瘤。考虑到成年人
干细胞协调组织适应并驱动肿瘤发生,了解介导
它们对禁食的反应对于增强损伤或衰老后的组织修复具有重要意义,
细胞功能下降,并可能为癌症提供新的治疗方法。在小鼠肠道中,
LGR 5+肠干细胞(ISCs)驱动肠内膜的快速更新,我们发现禁食
通过诱导过氧化物酶体增殖物激活受体δ(PPARd)驱动的脂肪酸
氧化(FAO)程序,其将游离脂肪酸分解成乙酰辅酶A单元。这项工作提出了关键的
关于禁食如何通过FAO途径调节肠道干性的问题。我们假设
β-羟基丁酸(βOHB)是粮农组织的一种酮体和生物合成产物,
辅酶A作为信号代谢物和能量底物,介导ISC禁食
反应为了支持这一观点,我们最近发现LGR 5 + ISCs强烈表达LGR 5的酶。
产生βOHB生酮途径,包括其限速酶HMGCS 2(3-羟基-3-
甲基戊二酰辅酶A合成酶2),与非干细胞群体相比,禁食强烈提高
ISC中的HMGCS 2和βOHB水平。小肠中的HMGCS 2损失降低LGR 5 + ISC中的βOHB水平
并使它们的分化偏向分泌细胞的命运,我们表明,外源性
βOHB和I类组蛋白脱乙酰酶(HDAC)抑制剂治疗。从机制上讲,βOHB作为一种
通过抑制HDAC介导的转录,
镇压因此,动态控制ISCs中的βOHB水平可以使ISCs快速适应
肠道到不同的生理状态,如禁食。许多重要的问题构成了我们目标的基础
关于酮体在ISC中作为空腹反应效应物的作用,
βOHB在这一过程中的体内信号传导(Aim 1)和能量(Aim 2)作用。另一个关键问题是,
解读ISCs中禁食诱导的FAO程序如何影响肿瘤的发生和进展(目标3)。
!
项目成果
期刊论文数量(1)
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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Omer Yilmaz其他文献
Omer Yilmaz的其他文献
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{{ truncateString('Omer Yilmaz', 18)}}的其他基金
Impact of fasting on intestinal stem cells and cancer
禁食对肠道干细胞和癌症的影响
- 批准号:
10238167 - 财政年份:2020
- 资助金额:
$ 37.79万 - 项目类别:
Impact of fasting on intestinal stem cells and cancer
禁食对肠道干细胞和癌症的影响
- 批准号:
10403548 - 财政年份:2020
- 资助金额:
$ 37.79万 - 项目类别:
Dietary control of stem cells in physiology and cancer
生理学和癌症中干细胞的饮食控制
- 批准号:
9213850 - 财政年份:2016
- 资助金额:
$ 37.79万 - 项目类别:
Dietary control of stem cells in physiology and cancer
生理学和癌症中干细胞的饮食控制
- 批准号:
10058815 - 财政年份:2016
- 资助金额:
$ 37.79万 - 项目类别:
Regulation of the Intestinal Stem Cell Niche in Aging
衰老过程中肠道干细胞生态位的调节
- 批准号:
8919197 - 财政年份:2014
- 资助金额:
$ 37.79万 - 项目类别:
Regulation of the Intestinal Stem Cell Niche in Aging
衰老过程中肠道干细胞生态位的调节
- 批准号:
8900580 - 财政年份:2014
- 资助金额:
$ 37.79万 - 项目类别:
Regulation of the Intestinal Stem Cell Niche in Aging
衰老过程中肠道干细胞生态位的调节
- 批准号:
8560030 - 财政年份:2013
- 资助金额:
$ 37.79万 - 项目类别:
Regulation of the Intestinal Stem Cell Niche in Aging
衰老过程中肠道干细胞生态位的调节
- 批准号:
8726277 - 财政年份:2013
- 资助金额:
$ 37.79万 - 项目类别:
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