ThisproposalaimstoelucidatetheroleofD52-mediatedanterogradeendosomaltraffickingduring physiologicalandpathologicalconditionsoftheexocrinepancreas.Acinarcells,theprimarycelltypeofthe exocrinepancreas,areresponsiblefortheregulatedsynthesisandsecretionofinactivedigestiveenzymes (zymogens).Intracellularactivationofzymogensleadstoacinarcelldamageandpancreatitis,anextremely painfulinflammatorydiseaseoftheexocrinepancreaswithlittleornotreatmentoptionsotherthanpalliative care1?3.Acinarcelldamageinitiatestranscriptionalreprogrammingtoaproliferativestem-celllikeprogenitorin aprocesstermedacinartoductalmetaplasia(ADM)4,5.Whilethisresponseisessentialforglandrepair,the progenitorcellsaresusceptibletomalignanttransformationandprogressiontowardpancreaticcancer5.Loss ofanterogradeendosomaltraffickingduringpancreatitishasbeenidentifiedasamajorpathogenicevent leadingtoacinardamageinexvivoacinarcultures6.Additionally,preliminarystudieshaveestablishedastrong linkbetweenthemaintenanceofanterogradeendosomaltraffickingandcontrolofacinarcelldifferentiation;? indicatingthatlossofthispathwayisacriticaleventinthelossofacinarterminaldifferentiationduring pathology.Thisproposalwillexamininghowtheanterogradeendosomalsecretorypathwaycontrolsacinarcell fateinvivousinganacinar-specific,induciblemousemodelofD52deletion.
Aim1 willassessthe morphologicalandfunctionalconsequenceofacinar-specificD52deletionintheadultmurinepancreas.
Aim2 willstudytheeffectofacinar-specificD52deletiononpancreatitisonset,progressionandrecoveryinrodents. Effectswillbeassessedatawholebody,organ,andcellularleveltofullycomprehendthemechanismsatplay. Animalswillbemonitoredforphenotypicchangesingeneralhealth,pancreaticinsufficiency,andacinar damage.Presenceofedema,inflammatorycellinfiltration,andfibrosiswithinthepancreaswillbedetermined toquantifypathology.Aciniwillbeisolatedtoevaluatemorphology,differentiationstatus,secretoryactivity andpolarity,unfoldedproteinresponseactivation,andpresenceofmembranetraffickingpathways.Finally, cellularmarkersofpancreatitiswillbeexamined.Basedonexvivowork,itishypothesizedthatlossofD52- mediatedanterogradeendosomaltraffickingwillinhibitterminaldifferentiationofacinarcells,exacerbating pathologicalconditions.Theroleoftheendosomalsysteminacinardifferentiationisayetunexploredareaof acinarbiology,representingapreviouslyunrecognizedmechanismforpreservingacinarcellfunctionandthe potentialfornewavenuesofpancreatitistreatment.Thecellularandmolecularmechanismsdrivingacinarcell dedifferentiationandredifferentiationduringglandrepairarestillemergingandrepresentacriticalvoidinour understandingofpancreaticdisease.Thisproposalisdesignedtoprovidebasicmechanisticinsightinto terminalacinardifferentiationunderbothphysiologicalandpathologicalconditions,fittingwellwithinthe missionoftheNIHtodiscoverfundamentalknowledgeofhumanhealthanddisease.

Public Health Relevance

Pancreatitis,anextremelypainfuldiseaseoftheexocrinepancreaswithlittletonotreatmentoptions, originateswithintheprimarycelltypeofthegland,acinarcells,asdigestiveenzymesbecomeprematurely activatedresultinginauto-digestionofthepancreas1?3.Therepairresponseessentialforglandregeneration rendersthepancreassusceptibletomalignanttransformationandprogressiontowardpancreaticcancer5.We haveidentifiedapreviouslyunrecognizedroleforendosomaltraffickinginmaintenanceofacinarcell physiology;?understandingthesemolecularmechanismsmayallowforthedevelopmentoftreatmentsand preventativetherapiesforthemajordiseasesoftheexocrinepancreas.

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 #
1F31DK111140-01
Application #
9192616
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (M1)L)
Program Officer
Densmore, Christine L
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$31,924
Indirect Cost
Name
University of Wisconsin Madison
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715