Abstract

Thepancreaticislet,amajorregulatorofglucosemetabolism,receivesarichsensoryinnervation.Sensory innervationofvisceralorgansisanimportantcomponentforpropermaintenanceofbodyhomeostasis. Visceralstimuliaredetectedbyfreenerveendingsofthevagusnerveandaretransmittedtothehindbrainvia sensoryneurons.Anewtherapeuticapproachofvagusnerveblockadeisunderclinicaltrialfortreatmentof morbidobesity.Vagalnervestimulationisfurtherusedtotreatschizophreniaanddepression.However,the signalsthatactivatevagalsensoryneuronsinthepancreaticisletandhowtheyaffectglucosemetabolismare notknown.Thelong-termgoalofthisresearchprojectistounderstandthecontributionofsensoryinnervation toisletfunctionandglucosemetabolism.Theobjectiveofthisapplicationistoidentifyandcharacterizethe molecularandfunctionalfeaturesofvagalsensoryneuronsinnervatingtheisletandtheireffectsonislet function.Thehypothesisisthatvagalsensoryneuronsinnervatingthepancreaticislet(1)transmit chemosensoryinflammatoryinformationfromtheislettoautonomiccentersinthebrainand(2)inflammatory processesintheisletinfluenceexcitabilityofsensoryneurons.Weproposethatexcessiveactivationofthe vagusnervepromotesisletinflammationandleadstodysregulationofglucosemetabolism,anunwantedside effectofvagalnervestimulationtherapythatshouldbestrictlyavoided.Therationalefortheproposed researchisthattheresultswillcontributeamissing,fundamentalelementofbasicknowledge,withoutwhich thecontributionofvisceralsensoryinnervationtoglucosemetabolismcannotbeunderstood.Thefindingswill alsohaveclinicalimplicationsforthetherapeutictreatmentthatinvolvesvagusnervestimulationorblockade. TheproposedresearchisthereforerelevanttothemissionoftheNIHthatpertainstothepursuitof fundamentalknowledgeaboutthenatureandbehavioroflivingsystems.Guidedbypreliminarydata,Iwilltest myhypothesisbypursuingtwospecificaims:(1)Toidentifythemolecularexpressionprofileofvagalsensory neuronsthatinnervatethepancreaticisletand(2)toidentifytheresponseprofileofvagalsensoryneurons undernormalphysiologicalandinflammatoryconditions.Underthefirstaim,Iwillidentifythemolecular markersfortheislet-specificvagalsensoryneuronsbyusingsinglecellmRNAanalysiswithFluidigm technology.Underthesecondaim,Iwillidentifywhatstimuliactivateislet-specificsensoryneuronsusingin situCa2+imagingofnodoseanddorsalrootgangliaexplantsandoflivingpancreaticslices.Theproposed researchissignificantbecauseitwillprovideinsightintopancreaticsensoryinnervationanditscontributionto glucosemetabolism.

Public Health Relevance

Thepancreaticisletisanorgancomposedofhighlyspecializedcellsthatsecreteinsulinandglucagon, thehormonesthatregulateglucosemetabolismandbloodsugarlevels.Dysregulationofthese hormonesleadstodiabetes,themostcommonchronicdiseaseintheworld.Releaseofislethormones ispartiallyregulatedbythenervoussystem.Thepancreaticisletisinnervatedbysensoryneuronsof thevagusnerve,buttheeffectofsensoryinnervationonisletphysiologyremainsunknown. Furthermore,externalstimulationofthevagusnerveisatherapeuticapproachtotreatrheumatoid arthritisandseveralotherconditions,butwestilldon?tunderstandhowthistreatmentaffectsglucose metabolismandwhetheritcanbeusedtomanagediabetes.Theproposedworkwouldhelpexplain howsensoryinnervationimpactsglucosemetabolismandhowitinfluencesdiabetespathogenesis..

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK112596-03
Application #
9604804
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2016-12-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146