Targeting ADAM17 activity for correction of vascular insulin resistance in type 2 diabetes
靶向 ADAM17 活性纠正 2 型糖尿病血管胰岛素抵抗
基本信息
- 批准号:10359775
- 负责人:
- 金额:$ 68.15万
- 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:2021-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AbdomenAmericanAnimal ModelArteriesBiopsyBlood VesselsBlood flowCardiovascular DiseasesCardiovascular systemCell membraneCell surfaceClinical TrialsDataDefectDiabetes MellitusDouble-Blind MethodDown-RegulationEndothelial CellsEndotheliumEnzymesExhibitsGlucose ClampGoalsHarvestHealthcareHumanImpairmentInsulinInsulin ReceptorInsulin ResistanceInsulin Signaling PathwayIntegral Membrane ProteinInterventionLegMatrix MetalloproteinasesMediatingMetabolic DiseasesMethodologyNitric OxideNon-Insulin-Dependent Diabetes MellitusOperative Surgical ProceduresOral AdministrationPathogenesisPatientsPhosphatidylserinesPrecipitating FactorsPrevalenceProductionProtein Kinase CPublishingRandomizedResearchResistanceRoleSkeletal MuscleSurfaceTestingTherapeuticTissuesTreatment EfficacyVascular EndotheliumVasodilationVasodilator AgentsWorkbaseblood glucose regulationexperimental studyextracellulargenetic manipulationglucose uptakeglycemic controlimprovedinhibitorinnovationinsulin sensitivityinsulin signalingloss of functionnon-diabeticnovelnovel therapeutic interventionoverexpressionpreservationpreventreceptorresponsetherapeutic developmentvascular bed
项目摘要
PROJECT SUMMARY/ABSTRACT
Vascular insulin resistance is a hallmark of type 2 diabetes (T2D) and dampening of insulin-induced
vasodilation is its primary consequence. Notably, in T2D, reduced insulin-stimulated vasodilation and blood
flow to tissues such as skeletal muscle significantly limits glucose uptake and contributes to impaired glucose
control. A detailed understanding of the precipitating factors and mechanisms underlying the defects in
vasodilator actions of insulin is critical for the development of therapeutic strategies aimed at improving
glycemic control and protecting against cardiovascular disease. Based on our prior work and most recent and
exciting preliminary data, we propose the novel hypothesis that ADAM17-mediated shedding of the insulin
receptor alpha (IRα) from endothelial cells impairs insulin-stimulated vasodilation in T2D. We further propose
that the increased activity of endothelial ADAM17 is attributed to protein kinase-C (PKC) activation and
subsequent externalization of phosphatidylserine (PS) to the outer leaflet of the cell membrane, which serves
to guide ADAM17 to its targeted substrates. As exogenous PS is a competitive inhibitor of ADAM17 sheddase
activity, we will also determine the efficacy of oral administration of PS for restoring vascular insulin sensitivity
in T2D patients. We will test our innovative hypotheses with gain- and loss-of-function genetic-manipulation
experiments in human cultured endothelial cells, in isolated resistance arteries harvested from patients
undergoing abdominal surgery, and in patients with T2D. Experimental results will determine the role of PS
externalization-ADAM17 activation-IRα shedding as a mechanism impairing the vasodilatory actions of insulin
in T2D. Specifically, in Aim 1, we will determine the mechanism by which PKC causes the externalization of
PS and whether PS externalization is needed for PKC-dependent activation of ADAM17 in endothelial cells.
Next, in Aim 2, we will determine the role of ADAM17 activity in IRα shedding and subsequent impairment of
insulin-stimulated vasodilation in T2D. Finally, in Aim 3, we will perform a randomized double-blind clinical trial
to determine the therapeutic efficacy of oral administration of the competitive inhibitor of ADAM17 sheddase
activity, PS, on insulin-stimulated leg blood flow in patients with T2D. Our team is poised to move
cardiovascular and diabetes research forward with a project that will exert a sustained, powerful impact across
a number of levels of inquiry that are novel conceptually, mechanistically, methodologically, and
therapeutically. Indeed, this proposal represents a paradigm shift from our current mechanistic understanding
of vascular insulin resistance. Targeting ADAM17 activation holds extraordinary promise for correcting
vascular insulin resistance and ultimately preventing/treating T2D-associated metabolic and cardiovascular
diseases.
项目总结/文摘
项目成果
期刊论文数量(0)
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Luis A Martinez-Lemus其他文献
Luis A Martinez-Lemus的其他文献
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{{ truncateString('Luis A Martinez-Lemus', 18)}}的其他基金
Role of neuraminidase activity on endothelial dysfunction in type 2 diabetes
神经氨酸酶活性对 2 型糖尿病内皮功能障碍的作用
- 批准号:
10207884 - 财政年份:2021
- 资助金额:
$ 68.15万 - 项目类别:
Targeting ADAM17 activity for correction of vascular insulin resistance in type 2 diabetes
靶向 ADAM17 活性纠正 2 型糖尿病血管胰岛素抵抗
- 批准号:
10569599 - 财政年份:2021
- 资助金额:
$ 68.15万 - 项目类别:
Role of neuraminidase activity on endothelial dysfunction in type 2 diabetes
神经氨酸酶活性对 2 型糖尿病内皮功能障碍的作用
- 批准号:
10642932 - 财政年份:2021
- 资助金额:
$ 68.15万 - 项目类别:
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