Despitetheclinicalandpsychosocialburdenofitchinatopicdermatitis(AD),effectivetreatmentoptions arelimited.Interleukin-31(IL-31),aninflammatoryfactorproducedbyskinTcells,hasemergedasapowerful mediatorofbothitchandrash.Whenadministeredtoskin,IL-31cantriggerdermatitisandactivatecutaneous afferent sensory nerves to drive scratching behavior. Therapeutic antibodies directed against IL-31 and its receptor,IL31RA,haveshownpromiseinclinicaltrialsforADandchronicpruritus.Yetfundamentalquestions about IL-31 biology remain. Which cells make IL-31? What pathways does IL-31 actuate in sensory afferent neurons? How do IL-31 signals integrate with other pruritogenic pathways in the context of inflammation? Improved definitions of the sources, pathways, and effector functions of IL-31 will substantially advance mechanisticunderstandingofthelinksbetweeninflammationanditch. Dr.Fassett?slong-termresearchgoalistoelucidatecellularandmolecularmechanismsresponsiblefor atopy-associatedpruritus.Theobjectiveofthisproposalistousegeneticmousemodelstoaddresstheinvivo biologyofIL-31byexaminingtheeffectsofendogenousIL-31oncutaneousinflammationandpruritussensory pathways. Dr. Fassett?s central hypothesis is that IL-31 couples itch and rash via its combined effects on pruritoceptive afferent pathways and cutaneous Th2 cytokine-mediated inflammation. Dr. Fassett will test this hypothesis using three specific aims.
In Aim 1, Dr. Fassett will use novel IL31-deficient animals and IL31- tdTomatoreporteranimalstodeterminehowmultipleIL-31sourcecelltypesfunctionallyimpactcutaneousTh2 inflammation in vivo.
In Aim 2, she will elucidate the contribution of IL-31:IL31RA to atopy-associated pruritoceptivepathwaysincludingitchsensationandneurogenicinflammation.
In Aim3, shewilldeterminehow IL-31 alters afferent responses to other pruritogens, including Th2 cytokines. This project is relevant to the mission of NIAMS because it explores the mechanism of action of IL-31, a biologic target of potentially great therapeuticvalueforatopicdermatitisandforpruritusassociatedwithotherinflammatoryskindiseases. Dr.FassettisanMDPhD-trainedDermatologistworkingasapost-doctoralresearchfellowattheUniversity ofCalifornia,SanFrancisco.SheisapplyingforaK08Awardtosupporthergoalofbecominganindependent physician scientist. UCSF?s exceptional training environment will support her efforts. Critical elements of her careerdevelopmentplanincludementorshipbyDr.MarkAnsel,expertincytokinebiologyandTh2inflammation;? co-mentorshipbyDr.AllanBasbaum,expertinpainanditch;?guidancebyamultidisciplinaryadvisorycommittee including senior physician-scientists;? coursework in advanced experimental neuroscience;? and professional development activities. Taken together, this career development plan will provide Dr. Fassett with a strong foundationonwhichtobuildhergrowingexpertiseintheneuroimmunepathwaysthatcoupleitchandrash.
Atopicdermatitisisanitchychronicinflammatoryskindiseaseprevalentamongchildrenandadults.Theatopic dermatitis-associatedcytokineIL-31contributestobothskininflammationanditchsensation,butitscellular sourcesandmechanismsofactionarenotwellcharacterized.Weproposetousenovelmousegenetictoolsto mapIL-31expressionpatternsandfunctionallydefinespecificmolecularpathwaysthatlinkinflammatorycells toIL-31-responsiveitchpathwaysinskin.
