Thegoalofthisresearchistoidentifythemechanismsbywhicheccrineglandsareformedwith theultimateaimofregeneratingeccrineglandsindamagedhumanskinorinvitrogenerated skingrafts.WehavedevelopedatransgenicmouselinethatallowsinducibleexpressionofEn1 intheepidermisandhaveshownthatinductionofEn1duringanarrowtimewindow surroundingtheinitiationofcutaneousappendagedevelopmentintheregionbetweenthe footpadsofanewbornmouseissufficienttoachieveacompletehomeoticconversionof cutaneousappendages,normallyhairfolliclesinthisregion,toeccrinesweatglands.Wewill exploitthismousetoidentifythegeneticpathwaysthatspecifyeccrineglanddevelopment insteadofhairfollicleformationfromacommonepidermalplacode.TheeffectsofforcedEn1 expressiononinductivesignalingfromthedermisandongeneexpressionintheepidermis beforeandafterplacodeinductionwillbecharacterized.ChIPmentationwillbeusedtoidentify thesubsetofthesegenesthataredirectlyregulatedbyEn1andproximalmediatorsofthis effect.Theoutcomeofthisresearchwillincludetheidentificationofthegeneticpathwaysthat specifythedistinctivedevelopmentalpathoftheeccrineglandplacodeandthedermalsignals thatinitiatethisprocess.TheapproachalsoteststwoalternativemodelsofEn1action.Ifoneof thesealternativesissupported,itwillbeaparadigm-shiftingoutcomethatemphasizestherole oftheepidermisinappendagefatechoice.Iftheotherissupported,itwillnonethelessadvance thefieldbyhelpingtoidentifytheuniquecomponentsoftheinductivesignalfromthedermis thatdriveEGdevelopment.

Public Health Relevance

Sweatglandsareessentialforthermoregulationbutdonotregeneratewhenskinis damaged.Thisprojectwillidentifythemolecularsignalsandresponsepathwaysthat specifysweatglanddevelopmentwiththeultimategoalofenablingtheregenerationof sweatglandsindamagedhumanskin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR074748-01
Application #
9659746
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2018-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114