Notch, Type 2 Diabetes and NAFLD
Notch、2 型糖尿病和 NAFLD
基本信息
- 批准号:9981180
- 负责人:
- 金额:$ 52.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectCellsChronic DiseaseCompensatory HyperinsulinemiaDataDecision MakingDevelopmentDietElementsEtiologyFOXO1A geneFastingFatty LiverFibrosisGeneticGenetic TranscriptionGlucose IntoleranceGoalsGrantHepaticHepatocyteHigh Fat DietHyperglycemiaITGAM geneImmuneIn VitroInflammatoryInsulinInsulin ReceptorInsulin ResistanceKineticsKnockout MiceKupffer CellsLigandsLightLiverMediatingMessenger RNAMetabolicMethylationModelingModernizationMolecularMusMyelogenousNon-Insulin-Dependent Diabetes MellitusObese MiceObesityPTPRC genePathogenicityPathologyPathway interactionsPatientsPhagocytesPharmaceutical PreparationsPharmacologyPhenotypePhosphoric Monoester HydrolasesPhosphorylationProcessProtein FamilyProteinsPublic HealthReceptor ActivationRegenerative responseReportingSignal TransductionStimulusSuggestionTestingTherapeuticTissuesTranslationschronic liver diseasecombatcomorbiditydemethylationdesignfeedinggain of functionglucose productionglucose toleranceimprovedinhibitor/antagonistjagged1 proteinlipid biosynthesisliver inflammationliver transplantationloss of functionmRNA Stabilitymacrophagemouse modelnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnotch proteinnovelnovel therapeuticsoverexpressionpandemic diseaseresponseresponse to injurystemtool
项目摘要
Abstract
The obesity pandemic brings with it multiple attendant metabolic comorbidities, including Type 2 Diabetes
(T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD). Both T2D and NAFLD are inadequately treated with
currently available therapy; although multiple medications are approved for T2D, few address the underlying
problem – insulin resistance. In addition, no medications are approved for NAFLD, the leading cause of chronic
liver disease and fastest-growing reason for liver transplantation. Clearly, a wider net for potential therapeutics
must be cast in order to stem the tide of obesity-related illness.
Notch is a highly conserved family of proteins critical for cell fate decision-making, but less is known about
Notch action in mature tissue. We have shown that Notch signaling is present at low levels in normal liver, but
increased markedly in livers from diet-induced or genetic mouse models of obesity, and similarly in obese
patients with T2D or NAFLD. Increased Notch signaling was found in hepatocytes and immune cells, but not
other nonparenchymal liver cells. Next, to test causality, we generated mice lacking hepatocyte Notch signaling
– these mice, when challenged with high-fat diet feeding, showed improved glucose tolerance and a parallel
decrease in hepatic steatosis. Conversely, mice with constitutive hepatocyte Notch activity showed glucose
intolerance and fatty liver even when fed normal chow diet. We observed similar effects in Notch loss- and
gain-of-function mice fed a novel fibrosis-provoking diet. Here, we will examine the mechanisms underlying
activation of hepatic Notch signaling, and downstream effectors of this maladaptive response, with ultimate
objective to ameliorate obesity-induced metabolic complications. In Aim 1, we will determine if increased Jag1
and Notch1 expression in signal-sending and -receiving hepatocytes, potentially due to parallel increase in Fto
and FoxO1 activity in the insulin-resistant liver, coordinate increased liver Notch activity and downstream
pathology in obesity. In Aim 2, we test how Notch activity leads to fatty liver, with the hypothesis that Notch-
induced PHLPP2 degradation allows unchecked insulin action and persistent de novo lipogenesis. Finally, in
Aim 3, we elucidate mechanism and repercussions of the additional increased Notch activity in hepatic
macrophages in obesity. Achieving the goals of this application will identify the underlying mechanism of
increased liver Notch signaling in obesity, delineate mechanistic determinants of Notch-induced lipogenesis,
and may uncover the potential use of Notch inhibitors for treatment of T2D and NAFLD.
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 }}
Utpal Pajvani其他文献
Utpal Pajvani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('Utpal Pajvani', 18)}}的其他基金
Beta cell Notch activity in Type 2 Diabetes
2 型糖尿病中的 Beta 细胞 Notch 活性
- 批准号:
10592434 - 财政年份:2022
- 资助金额:
$ 52.1万 - 项目类别:
Jagged-Notch signaling in NASH/fibrosis
NASH/纤维化中的锯齿状Notch信号传导
- 批准号:
10744371 - 财政年份:2019
- 资助金额:
$ 52.1万 - 项目类别:
Jagged-Notch signaling in NASH/fibrosis
NASH/纤维化中的锯齿状Notch信号传导
- 批准号:
10338130 - 财政年份:2019
- 资助金额:
$ 52.1万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 52.1万 - 项目类别:
Research Grant














{{item.name}}会员




