Project Grant F32AI203319

LEVERAGING MICRONEEDLES TO MODULATE KERATINOCYTE SIGNALING AND PROMOTE IMMUNE TOLERANCE - PROJECT SUMMARY/ABSTRACT MULTIPLE SCLEROSIS (MS) IS A WORLDWIDE DISEASE, CURRENTLY AFFECTING 2.9 MILLION PEOPLE. MECHANISTICALLY, MS IS AN AUTOIMMUNE DISEASE PROPAGATED BY SELF-REACTIVE T CELLS THAT RECOGNIZE AND ATTACK THE MYELIN OLIGODENDROCYTE GLYCOPROTEIN (MOG), INSULATING THE NEURONS OF THE CENTRAL NERVOUS SYSTEM. CURRENT TREATMENTS, INCLUDING DISEASE MODIFYING THERAPIES AND SYSTEMIC IMMUNE SUPPRESSANTS, TREAT SYMPTOMS RATHER THAN TOLERIZING REACTIVE T CELLS. OVERACTIVE INNATE IMMUNE SIGNALING HAS RECENTLY BEEN IDENTIFIED AS A TARGET FOR TREATING AUTOIMMUNE DISEASES. TOLL-LIKE RECEPTOR (TLR) SIGNALING IS A KEY PLAYER IN INNATE SIGNALING, AND IT HAS BEEN SHOWN THAT BLOCKING TLRS CAN REDUCE AUTOIMMUNE INFLAMMATION. TLR SIGNALING IS HIGHLY PREVALENT IN THE SKIN, A BARRIER IMMUNE TISSUE THAT FUNCTIONS TO PROBE THE ENVIRONMENT AND MODERATE THE IMMUNE RESPONSE TO THE OUTSIDE WORLD. IMPORTANTLY, THE EPITHELIAL CELLS, KERATINOCYTES (KC), THAT COMPRISE THIS CONNECTIVE BARRIER SHAPE THE SKIN-IMMUNE ENVIRONMENT THROUGH IMMUNE SIGNALING MECHANISMS, SUCH AS TLR-INDUCED SECRETION OF CYTOKINES/CHEMOKINES. THE WORK PROPOSED HERE WILL INVESTIGATE KCS AS A THERAPEUTIC TARGET OF TLR ANTAGONISTS IN THE CONTEXT OF SKIN DELIVERY TO PROMOTE IMMUNE TOLERANCE. BY HARNESSING THE KC SIGNALING IN SKIN, THIS WORK WILL INFORM THE DESIGN OF NOVEL IMMUNOMODULATING THERAPIES TO TREAT MS AND ULTIMATELY OTHER AUTOIMMUNE DISEASES. WE HAVE DEVELOPED A 3D, DISSOLVABLE MICRONEEDLE ARRAY (MNA) PLATFORM TO TARGET THE SKIN AND MODULATE THE IMMUNE RESPONSE THROUGH LOADED IMMUNE SIGNALING MOLECULES. THESE MNAS GENERATE ANTIGEN-SPECIFIC TOLERANCE AND STOP AUTOIMMUNE DISEASE IN MOUSE MODELS OF MS. IN PILOT STUDIES, WE HAVE OBSERVED TRANSCRIPTIONAL CHANGES IN THE SKIN THAT IMPLICATE KC AND IMMUNE CELL SIGNALING POST-MNA APPLICATION. IN THE PROPOSED RESEARCH, I WILL INVESTIGATE IMMUNE SIGNALING IN THE SKIN THROUGH TWO AIMS, UTILIZING BOTH IN VITRO AND IN VIVO SYSTEMS TO MAP THE KC RESPONSE TO MNAS. AIM 1 WILL USE IN VITRO ASSAYS TO TEST THE HYPOTHESIS THAT BLOCKING TLRS IN KCS REDUCES KC ACTIVATION AND MEDIATES DOWNSTREAM TOLERANCE IN T CELLS. AIM 2 WILL THEN INVESTIGATE THE ROLE OF KC SIGNALING IN IMMUNE CELL RECRUITMENT/ACTIVATION IN VIVO. TOGETHER, THESE STUDIES WILL DEMONSTRATE THAT THE INHIBITION OF INNATE IMMUNE SIGNALING IN KCS CAN BE PAIRED WITH MNAS TO BE A POWERFUL PLATFORM TO PROMOTE IMMUNE TOLERANCE. CONCURRENTLY, MY F32 EFFORTS WILL ADDRESS GAPS IN MY TRAINING. I WILL I) DEVELOP NEW IMMUNOLOGICAL SKILLS, II.) EXPAND MY EXPERTISE IN TEACHING/MENTORING, AND III.) PREPARE FOR ACADEMIC INDEPENDENCE. THE WORK PROPOSED WILL BE COMPLETED IN THE JEWELL LAB, SITUATED WITHIN THE FISCHELL INSTITUTE FOR BIOMEDICAL DEVICES. NOT ONLY IS THIS ENVIRONMENT HEAVILY COLLABORATIVE, BUT I HAVE ACCESS TO TOOLS, TRAINING, AND MENTORSHIP TO SHAPE BOTH MY SCIENTIFIC AND CAREER GROWTH. ADDITIONALLY, WITH THE SUPPORT OF MY CAREER DEVELOPMENT COMMITTEE, COMBINED WITH THE SUPPORT OF THE F32, THE PROPOSED TRAINING WILL PROPEL MY GOAL OF BECOMING AN INDEPENDENT SCIENTIST AND MENTOR AT THE FOREFRONT OF DRUG DELIVERY AND IMMUNO-ENGINEERING.