Enteroendocrine Regulation of Intestinal Metabolism
肠道代谢的肠内分泌调节
基本信息
- 批准号:10301046
- 负责人:
- 金额:$ 12.7万
- 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:2021-09-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAffectBiochemistryBiological AssayBiological ModelsBrainCarbon DioxideCell CommunicationCell LineCellsCommunitiesCommunity PhysicianCoupledDataDevelopmentDevelopmental BiologyDiarrheaDietary intakeDigestionDigestive System DisordersDistressElectrophysiology (science)EndocrinologyEnsureEnterocytesEnteroendocrine CellEnvironmentEpithelialEpithelial CellsExhibitsFRAP1 geneFluorescenceG-Protein-Coupled ReceptorsGastroenterologyGenetic TranscriptionGenus HippocampusGoalsHealthHomeHormonesHumanHungerImageIndividualIngestionInstitutionInternationalIntestinesIonsLinkMass Spectrum AnalysisMeasuresMedical centerMedicineMentorsMetabolicMetabolic DiseasesMetabolismMitochondriaMusMutationNational Institute of Diabetes and Digestive and Kidney DiseasesNausea and VomitingNon-Insulin-Dependent Diabetes MellitusNutrientOrganOrganoidsPancreasPaneth CellsParenteral NutritionPathway interactionsPediatric HospitalsPediatric ResearchPeptide Signal SequencesPeptidesPharmacologyPhysiologyPlayPluripotent Stem CellsProductionProtein KinasePublic HealthReceptor CellRegenerative capacityRegulationReporterResearchResearch PersonnelRespirationRoleSatiationScheduleScientistSecond Messenger SystemsSignal TransductionSmall IntestinesSystemTestingTimeTissuesTrainingUnited StatesUnited States National Institutes of HealthWorkbaseblood glucose regulationcell motilitycell typedetection of nutrientdietaryexperimental studygastrointestinalgut healthhormonal signalshuman modelinnovationinsulin secretionintestinal epitheliumintestinal homeostasismetabolic ratemetabolomicsmouse modelnovelnovel therapeuticsnutrient absorptionnutritionparacrineresponsesingle cell analysissingle-cell RNA sequencingstem cell nichestem cellssuccesstraining opportunitytranscription factoruptake
项目摘要
PROJECT SUMMARY
Dr. Heather McCauley is mentored by Dr. James Wells at Cincinnati Children’s Hospital Medical
Center (CCHMC), the largest pediatric research institution in the nation. CCHMC ranked 2nd in NIH support in
2017 and is home to an NIDDK-sponsored Digestive Diseases Research Center with a vibrant community of
physicians and scientists. CCHMC provides a very supportive training environment for young investigators. Dr.
McCauley proposes an innovative cross-disciplinary research plan which bridges developmental biology, stem
cell and organoid medicine, gastroenterology and nutrition, endocrinology, and metabolism.
Enteroendocrine cells (EECs) are specialized intestinal epithelial cells which secrete more than 20
bioactive peptides to regulate satiety, gut motility, glucose homeostasis, nutrient absorption, and whole-body
metabolism in response to ingested nutrients. While the systemic targets of EEC hormones are well known,
such as the brain and the pancreas, the role of EEC peptides in regulating the function of the intestine itself is
surprisingly understudied. Our lab has developed a unique, high-throughput human model system to test the
roles of individual EEC peptides on intestinal function by generating EEC-deficient human intestinal organoids
from pluripotent stem cells. We recently used this model system to show that some EECs regulate ion-coupled
nutrient absorption in neighboring cells. Because EECs are nutrient-sensing cells, we considered that they
might coordinate other intestinal responses to nutrient availability. Most EEC peptides signal via G-protein
coupled receptors which activate second messengers to modulate the function of their target cell. These
second messengers are intimately linked to ancient regulators of cellular metabolism, such as mammalian
target of rapamycin (mTOR), which are known to play essential roles in many intestinal functions. This
proposal will test the hypothesis that EECs regulate cellular metabolism in the stem cell niche (Aim 1) and in
the differentiated enterocyte (Aim 2), thus impacting both intestinal homeostasis and efficiency of nutrient
absorption. As EECs are now common targets for the treatment of type 2 diabetes, understanding how EECs
affect intestinal metabolism and function will inform how dietary or pharmacological manipulation of EECs will
impact gut health, nutrient absorption, and whole-body metabolism.
To ensure success of the proposed research strategy, Dr. McCauley requires additional mentored time
to become fluent in metabolic and metabolomic assays. Dr. McCauley has obtained a co-mentor, Dr. Kenneth
Setchell, an international expert in using Mass Spectrometry to understand nutrition- and digestive disease-
related changes in metabolism. Dr. McCauley proposes a rigorous yet feasible schedule of formal and informal
training opportunities in metabolomics. At the conclusion of the mentored portion of her training, Dr. McCauley
will be established as a fully independent, leading young investigator in the field of gastrointestinal metabolism,
a critically understudied niche in the GI community.
项目概要
Heather McCauley 博士由辛辛那提儿童医院医疗中心的 James Wells 博士指导
中心(CCHMC),全国最大的儿科研究机构。 CCHMC 在 NIH 支持中排名第二
2017 年成立,是 NIDDK 赞助的消化疾病研究中心的所在地,该中心拥有充满活力的社区
医生和科学家。 CCHMC 为年轻研究者提供了非常支持的培训环境。博士。
麦考利提出了一项创新的跨学科研究计划,该计划将发育生物学、干细胞
细胞和类器官医学、胃肠病学和营养学、内分泌学和新陈代谢。
肠内分泌细胞 (EEC) 是专门的肠上皮细胞,可分泌 20 多种
生物活性肽可调节饱腹感、肠道蠕动、葡萄糖稳态、营养吸收和全身
新陈代谢对摄入的营养物质作出反应。虽然 EEC 激素的全身靶标是众所周知的,
比如大脑和胰腺,EEC肽对肠道本身功能的调节作用是
令人惊讶的是,研究不足。我们的实验室开发了一种独特的高通量人体模型系统来测试
单个 EEC 肽通过生成 EEC 缺陷的人类肠道类器官对肠道功能的作用
来自多能干细胞。我们最近使用这个模型系统来表明一些 EEC 调节离子耦合
邻近细胞的营养吸收。由于 EEC 是营养敏感细胞,我们认为它们
可能协调其他肠道对营养可用性的反应。大多数 EEC 肽通过 G 蛋白发出信号
偶联受体激活第二信使以调节靶细胞的功能。这些
第二信使与古代细胞代谢调节因子密切相关,例如哺乳动物
雷帕霉素(mTOR)的靶标,已知其在许多肠道功能中发挥重要作用。这
该提案将检验以下假设:EEC 调节干细胞生态位中的细胞代谢(目标 1)和
分化的肠上皮细胞(目标 2),从而影响肠道稳态和营养效率
吸收。由于 EEC 现在是治疗 2 型糖尿病的常见靶点,因此了解 EEC 如何发挥作用
影响肠道代谢和功能将告知 EEC 的饮食或药物操作将如何
影响肠道健康、营养吸收和全身代谢。
为了确保拟议研究策略的成功,麦考利博士需要额外的指导时间
熟练掌握代谢和代谢组学检测。麦考利博士获得了一位共同导师肯尼思博士
Setchell,一位使用质谱来了解营养和消化疾病的国际专家
相关的新陈代谢变化。麦考利博士提出了一个严格但可行的正式和非正式时间表
代谢组学方面的培训机会。在培训的指导部分结束时,麦考利博士
将成为胃肠代谢领域完全独立、领先的年轻研究者,
地理标志界中一个尚未得到充分研究的利基市场。
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 }}
Heather A McCauley其他文献
Heather A McCauley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('Heather A McCauley', 18)}}的其他基金
Enteroendocrine Regulation of Intestinal Metabolism
肠道代谢的肠内分泌调节
- 批准号:
10816027 - 财政年份:2021
- 资助金额:
$ 12.7万 - 项目类别:
Enteroendocrine Regulation of Intestinal Metabolism
肠道代谢的肠内分泌调节
- 批准号:
10475157 - 财政年份:2021
- 资助金额:
$ 12.7万 - 项目类别:
相似海外基金
Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
- 批准号:
2867610 - 财政年份:2023
- 资助金额:
$ 12.7万 - 项目类别:
Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
- 批准号:
BB/W009633/1 - 财政年份:2022
- 资助金额:
$ 12.7万 - 项目类别:
Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2021
- 资助金额:
$ 12.7万 - 项目类别:
Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
- 批准号:
459043 - 财政年份:2021
- 资助金额:
$ 12.7万 - 项目类别:
Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2020
- 资助金额:
$ 12.7万 - 项目类别:
Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10561642 - 财政年份:2019
- 资助金额:
$ 12.7万 - 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2019
- 资助金额:
$ 12.7万 - 项目类别:
Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
- 批准号:
2243045 - 财政年份:2019
- 资助金额:
$ 12.7万 - 项目类别:
Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10359032 - 财政年份:2019
- 资助金额:
$ 12.7万 - 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
- 批准号:
428988 - 财政年份:2019
- 资助金额:
$ 12.7万 - 项目类别:
Studentship Programs