The Role of Arginine Transport on Pancreatic Alpha Cell Proliferation and Function
精氨酸转运对胰腺α细胞增殖和功能的作用
基本信息
- 批准号:10678248
- 负责人:
- 金额:$ 3.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlpha CellAmino Acid TransporterAmino AcidsArginineBasic Amino Acid Transport SystemsBloodCRISPR/Cas technologyCalciumCationsCause of DeathCell ProliferationCell physiologyCell secretionCellsChemicalsClinical TrialsCo-ImmunoprecipitationsDataDevelopmentDiabetes MellitusDisease ProgressionEndocrineEnvironmentEnzyme InhibitionFRAP1 geneFailureFeedbackFellowshipFunctional disorderFutureGlucagonGluconeogenesisGlucoseGlutamineHormone secretionHumanHyperglycemiaHyperplasiaImageImmunohistochemistryImpairmentIncubatedIndividualInsulinInsulin-Dependent Diabetes MellitusInterruptionIslets of LangerhansKnock-outKnockout MiceLiverMeasuresMembraneMentorsMentorshipMetabolismModelingModificationMolecularMonitorMusNitric OxideNitric Oxide PathwayNon-Insulin-Dependent Diabetes MellitusNutrientPathway interactionsPhysiologicalProductionProliferatingPropertyProteinsQualifyingRegulationResearchResourcesRodent ModelRoleScientistSignal TransductionStructure of alpha Cell of isletStructure of beta Cell of isletSystemTestingTherapeuticTissuesTrainingTransgenic MiceWestern BlottingWorkarginaseblood glucose regulationcalcium indicatorcareercombatexperimental studyhyperglucagonemiain vivo Modelinsulin secretionisletmouse modelnew therapeutic targetprotein protein interactionsensorsmall moleculetool
项目摘要
Project Summary
The training strategy demonstrated in this document will help me advance my career to be an
independent research scientist in the field of diabetes. I propose to assess the role of arginine transport in the
regulation of pancreatic islet cell proliferation and hormone secretion. Disease progression of diabetes is
attributed to the inability of pancreatic β-cells to sufficiently secrete insulin and the combined failure to suppress
pancreatic α-cell secretion of glucagon. Inhibition of glucagon signaling reduces hyperglycemia for individuals
with diabetes.3 However, impairment of glucagon signaling leads to hyperglucagonemia, hyperaminoacidemia,
and α-cell proliferation.4,5 Our lab has identified a liver-α-cell axis that contributes to α-cell proliferation through
the accumulation of amino acids in the blood.4 We have identified two major amino acids that contribute to α-cell
proliferation, glutamine4 and arginine (unpublished data). However, the mechanisms underlying arginine
transport in the α-cell specifically and its contribution to α-cell proliferation and secretion are not well defined.
The cationic amino acid transporter SLC7A2 is highly expressed in mouse and human pancreatic α-cells.
Therefore, we hypothesize that hyperaminoacidemia that results from interrupted glucagon signaling
contributes to increased arginine transport promoting α-cell proliferation and dysfunction. Our
preliminary studies show that SLC7A2 is required for α-cell proliferation and glucagon secretion even when
challenged with strong membrane depolarizing agents challenging current cation-centric models of arginine
stimulated secretion (Figure 2 and 4). Using a new α-cell specific Slc7a2 knockout mouse model, we will unravel
the molecular mechanisms that lead to arginine-stimulated α-cell proliferation and glucagon secretion. To assess
whether SLC7A2 in α-cells is necessary for amino acid-dependent α-cell proliferation, Slc7a2 knockout in
immortalized mouse αTC1-6 cells and an inducible α-cell specific Slc7a2 knockout mouse model will be used to
assess changes in α-cell proliferation and mass. Additionally, the mechanism of arginine-induced mTORC1
activation will be targeted to determine if arginine activates mTORC1 through the inactivation of the CASTOR1-
GATOR2 pathway (Aim 1). Furthermore, to test the ability for arginine transport via SLC7A2 to modulate
glucagon secretion we will combine tools used in Aim 1 with chemical and genetically encoded Ca2+ sensors to
observe changes in α-cell glucagon secretion. We will also measure nitric oxide levels, and test the affect of
nitric oxide on glucagon secretion to understand the mechanism behind arginine-induced glucagon secretion
(Aim 2). Successfully accomplishing this study will enhance our current understanding of amino acid-induced α-
cell proliferation and function, as well as broaden the possibilities of therapeutic treatments for diabetes. My
training will be achieved through the execution of this study utilizing the fantastic resources and facilities provided
by Vanderbilt and thorough mentorship from my highly qualified mentors, Drs. Danielle Dean and David
Jacobsen.
项目总结
项目成果
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