Mechanisms regulating neurotensin secretion and function
调节神经降压素分泌和功能的机制
基本信息
- 批准号:9219942
- 负责人:
- 金额:$ 44.02万
- 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:2017-02-01 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAdipose tissueAffinityAmino AcidsAssimilationsAttenuatedBiochemistryBiometryBody mass indexCellsClinicalColorectal CancerComplexComputational BiologyConsumptionDevelopmentDiabetes MellitusDiet therapyDietary FatsDigestionDistantDrosophila genusEndocrinologyEnterocytesEnteroendocrine CellEpidemiologyEpigenetic ProcessFRAP1 geneFastingFat BodyFatty LiverFatty acid glycerol estersFoodFutureGastrointestinal PhysiologyGenesGeneticGoalsGrowthHepatocyteHigh Fat DietHomeostasisHormonesHumanIngestionInnovative TherapyInsulin ResistanceIntestinal AbsorptionIntestinal MucosaIntestinesKnockout MiceLaboratoriesLeadLengthLinkLipidsLiverMAPK3 geneMalignant neoplasm of gastrointestinal tractMalignant neoplasm of pancreasMediatingMetabolic DiseasesMetabolismMidgutMolecularMorbidity - disease rateMusNeurotensinNeurotensin ReceptorsNonesterified Fatty AcidsNutrientObesityOvernutritionPeptidesPhysiologyPlayPopulation StudyProcessProtein KinaseRegulationRiskRoleSignal PathwaySignal TransductionSiteSmall IntestinesStimulusStomachSystemTimeTransgenic OrganismsWomanabsorptionbaseblood glucose regulationcardiovascular disorder riskcell motilitydisorder riskepidemiology studylipid metabolismmTOR inhibitionmalignant breast neoplasmmortalitymouse modelmultidisciplinarynon-alcoholic fatty livernoveloverexpressionreceptorresponsesortilinuptake
项目摘要
ABSTRACT
Neurotensin (NT) is a tridecapeptide localized to specialized enteroendocrine (EE) cells predominantly
in the small bowel. The most potent stimulus for NT release is the ingestion of dietary fats. NT facilitates free
fatty acid (FFA) absorption in the proximal intestine, stimulates growth of colorectal, pancreatic and breast
cancers that have the high affinity NT receptor 1 (NTR1), and contributes to lipid metabolism and glucose
control although its precise role in these processes has not been delineated. Recently, a large population
study identified a significant association of increased fasting pro-NT (a stable NT precursor fragment produced
in equimolar amounts relative to NT) levels with the development of diabetes, increased risk of cardiovascular
disease and mortality, and increased risk of breast cancer in women. Together, these findings identify an
important role for NT in lipid metabolism and, moreover, links increased NT levels to various metabolic
diseases and increased morbidity and mortality.
Epidemiological evidence clearly shows direct linkage between overnutrition and obesity; however, the
molecular mechanisms linking adiposity to overnutrition remain unknown. In exciting recent findings, we
demonstrate that NT deficiency (using an NT knockout mouse model) protects against obesity, insulin
resistance and non-alcoholic fatty liver disease (NAFLD) associated with high fat consumption; we further
demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FFA
absorption through a mechanism involving NTR1 and NTR3/sortilin. Conversely, the overexpression of NT in
Drosophila midgut EE cells increases lipid accumulation in the midgut, fat body and oenocytes (hepatocyte-like
cells). Remarkably, in humans, we show that increased levels of pro-NT strongly predict new onset obesity in
a graded manner, which is independent of body mass index (BMI) and insulin resistance. Therefore, the
central hypothesis for our current proposal is that FFA-mediated NT release by EE cells, through a cross-talk
mechanism involving AMPK activation, mTOR inhibition, and ERK1/2 activation, promotes intestinal absorption
of FFAs acting through NTR1 and/or NTR3 and the inhibition of intestinal AMPK. Moreover, we speculate that
the overconsumption of dietary fats, which leads to excess NT secretion, results in obesity (from continued fat
storage) and metabolic disorders (e.g., hepatic steatosis and insulin resistance). To examine our long-term
goal of better defining intestinal NT secretion and function, we have assembled a multidisciplinary and highly
collaborative team with defined expertise in NT physiology and function; metabolism and systems
biochemistry; Drosophila genetics; and, biostatistics/computational biology. Ultimately, our findings will: i)
significantly advance the fields of GI physiology, endocrinology and metabolism; ii) change existing paradigms
regarding the systemic effects of NT; and, iii) revolutionize our concept of gut hormones and their role in
obesity and metabolic diseases.
摘要
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 }}
Bernard Mark Evers其他文献
Bernard Mark Evers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('Bernard Mark Evers', 18)}}的其他基金
Targeting the Immunosuppressive Tumor Microenvironment for Colorectal Cancer Treatment
针对结直肠癌治疗的免疫抑制肿瘤微环境
- 批准号:
10748123 - 财政年份:2023
- 资助金额:
$ 44.02万 - 项目类别:
Appalachian Career Training in Oncology (ACTION) Program
阿巴拉契亚肿瘤学职业培训 (ACTION) 计划
- 批准号:
10001327 - 财政年份:2018
- 资助金额:
$ 44.02万 - 项目类别:
Appalachian Career Training in Oncology (ACTION) Program
阿巴拉契亚肿瘤学职业培训 (ACTION) 计划
- 批准号:
10245140 - 财政年份:2018
- 资助金额:
$ 44.02万 - 项目类别:
Appalachian Career Training in Oncology (ACTION) Program
阿巴拉契亚肿瘤学职业培训 (ACTION) 计划
- 批准号:
10475257 - 财政年份:2018
- 资助金额:
$ 44.02万 - 项目类别:
Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment
改变脂质代谢作为结肠癌治疗的新目标
- 批准号:
10227741 - 财政年份:2017
- 资助金额:
$ 44.02万 - 项目类别:
Mechanisms Regulating Neurotensin Secretion and Function
调节神经降压素分泌和功能的机制
- 批准号:
10536470 - 财政年份:2017
- 资助金额:
$ 44.02万 - 项目类别:
Mechanisms Regulating Neurotensin Secretion and Function
调节神经降压素分泌和功能的机制
- 批准号:
10651886 - 财政年份:2017
- 资助金额:
$ 44.02万 - 项目类别:
Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis
新型 pRNA 纳米颗粒递送作为结直肠癌转移的定向治疗
- 批准号:
9547788 - 财政年份:2015
- 资助金额:
$ 44.02万 - 项目类别:
Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis
新型 pRNA 纳米颗粒递送作为结直肠癌转移的定向治疗
- 批准号:
9753735 - 财政年份:2015
- 资助金额:
$ 44.02万 - 项目类别:
Cancer specific and organ-avoiding RNA architectures for quantitative imaging
用于定量成像的癌症特异性和器官回避 RNA 结构
- 批准号:
9208386 - 财政年份:2014
- 资助金额:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 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:
$ 44.02万 - 项目类别:
Studentship Programs