Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration
SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用
基本信息
- 批准号:10378332
- 负责人:
- 金额:$ 20.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-15 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:AdultB Cell ProliferationBeta CellBlood VesselsCDKN2A geneCell CycleCellular Metabolic ProcessDataDiabetes MellitusDietDiseaseEquilibriumEtiologyGeneticHomeostasisHumanImmuneImmune signalingIndividualInnate Immune SystemInsulinInsulin ResistanceKnockout MiceLaboratoriesLigandsLiverMEKsMediatingMetabolicMichiganModelingMolecularMusNatural ImmunityNatural regenerationNatureNuclearOrganismOvernutritionPatientsPeripheralPharmacologyQiRecombinantsRegenerative capacityRegulationReportingSignal PathwaySignal TransductionStimulusStructure of beta Cell of isletSystemTLR2 geneTLR4 geneTestingTherapeuticTimeUniversitiesWorkage relatedagedbeta cell replacementcell injurycell regenerationcell replacement therapydiabetes mellitus therapydiabetic patientdiabetogenicdiet-induced obesityefficacy testingemerging adultglycemic controlhealth applicationinfancyinnovationinsightisletmouse modelnew therapeutic targetnovelresponserestorationtranslational study
项目摘要
SUMMARY
Pancreatic β cell regeneration is a promising approach for the treatment of insulin dependent type-1 (T1D) and
-2 diabetes (T2D). However, the nature of the signaling pathway(s) responsible for the age-dependent decline
of β cell proliferation remains an enigma, a significant roadblock in diabetes therapy. The Kulkarni laboratory at
Joslin Diabetes Center recently reported that SerpinB1 secreted from the liver promotes β cell proliferation (El
Ouaamari et al. Cell Metabolism 2016) while the Qi laboratory at the University of Michigan showed that Toll-
Like Receptors 2 and 4 (TLR2/TLR4) signaling pathways, two redundant innate immune signaling pathways,
block diet-induced β cell replication (Nat Immunol, under revision). In this application, the Kulkarni and Qi
laboratories will team up to test an overarching hypothesis that the antagonistic interplay between SerpinB1
and TLR2/TLR4 maintains a balance in favor of β cell regeneration in both mice and humans under
diabetogenic stimuli. We propose that TLR2/TLR4 activation in diet-induced obesity blocks SerpinB1-mediated
β cell replication while simultaneous disruption of TLR2/TLR4 signaling pathways on β cells may promote β cell
proliferation via SerpinB1-dependent manner. To this end, we will (i) perform lineage tracing to test the
hypothesis that TLR2/TLR4 regulates β cell replication in a β cell autonomous manner; (ii) delineate the
interplay between TLR2/TLR4 and SerpinB1 and the underlying mechanism in the regulation of β cell
regeneration; and (iii) determine the therapeutic potential of targeting TLR2/TLR4 and SerpinB1 in β cell
proliferation and regeneration using human β cells and islets. Hence, this study will be instrumental in
demonstrating that metabolic and innate immune systems, two primitive systems critical for the long-term
homeostasis of multi-cellular organisms, have evolved to promote cooperative, adaptive responses against
diverse environmental challenges such as overnutrition. If successful, this study will help realize therapeutic
potential of our discoveries and benefit millions of diabetic patients worldwide by delivering novel, invaluable
therapeutics for the treatment of widespread diabetes.
RELEVANCE TO HUMAN HEALTH: This application, with parallel mouse models and human islets studies,
will reveal novel molecular and cellular mechanisms, shaped by metabolic and innate immunity signaling
pathways, which govern β cell replication and metabolic homeostasis. Hence, this study may fundamentally
change our views of metabolic-innate immune interactions, and hold tremendous promise to uncover both
novel disease mechanisms and pharmacological targets aimed at treating and reversing the underlying
metabolic imbalances in diabetes.
总结
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)
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ROHIT N. KULKARNI其他文献
ROHIT N. KULKARNI的其他文献
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{{ truncateString('ROHIT N. KULKARNI', 18)}}的其他基金
Interrogating the ubiquitin pathway to understand and treat cytokine-induced beta-cell death in type 1 diabetes
探究泛素通路以了解和治疗 1 型糖尿病中细胞因子诱导的 β 细胞死亡
- 批准号:
10278303 - 财政年份:2021
- 资助金额:
$ 20.53万 - 项目类别:
Interrogating the ubiquitin pathway to understand and treat cytokine-induced beta-cell death in type 1 diabetes
探究泛素通路以了解和治疗 1 型糖尿病中细胞因子诱导的 β 细胞死亡
- 批准号:
10477373 - 财政年份:2021
- 资助金额:
$ 20.53万 - 项目类别:
Enhanced pancreatic islet cell engraftment by treatment with serpin B1
丝氨酸蛋白酶抑制剂 B1 处理增强胰岛细胞植入
- 批准号:
10383270 - 财政年份:2021
- 资助金额:
$ 20.53万 - 项目类别:
Interplay between SerpinB1 and TLR2/TLR4 in beta cell regeneration
SerpinB1 和 TLR2/TLR4 在 β 细胞再生中的相互作用
- 批准号:
10094305 - 财政年份:2020
- 资助金额:
$ 20.53万 - 项目类别:
One-compound, one-islet: A high-throughput platform for small-molecule discovery
一种化合物,一种胰岛:用于小分子发现的高通量平台
- 批准号:
10450745 - 财政年份:2019
- 资助金额:
$ 20.53万 - 项目类别:
One-compound, one-islet: A high-throughput platform for small-molecule discovery
一种化合物,一种胰岛:用于小分子发现的高通量平台
- 批准号:
10356005 - 财政年份:2019
- 资助金额:
$ 20.53万 - 项目类别:
Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration
SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用
- 批准号:
10301008 - 财政年份:2018
- 资助金额:
$ 20.53万 - 项目类别:
Regulation of Autoimmune Type 1 Diabetes by Serpins B1 and A1 (Alpha 1-Antitrypsin)
Serpins B1 和 A1(α 1-抗胰蛋白酶)对自身免疫性 1 型糖尿病的调节
- 批准号:
9556000 - 财政年份:2018
- 资助金额:
$ 20.53万 - 项目类别:
Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration
SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用
- 批准号:
10062405 - 财政年份:2018
- 资助金额:
$ 20.53万 - 项目类别:
Role of 12-lipoxygenase and 12-HETE signaling in beta-cell dysfunction
12-脂氧合酶和 12-HETE 信号在 β 细胞功能障碍中的作用
- 批准号:
10058354 - 财政年份:2015
- 资助金额:
$ 20.53万 - 项目类别:
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