Project Grant K08AR084617

BIOCHEMICAL DETERMINANTS OF CHEMOKINE RECEPTOR SIGNALING - PROJECT SUMMARY I AM COMMITTED TO A CAREER AS A PHYSICIAN-SCIENTIST AND HAVE A KEEN INTEREST IN RECEPTOR BIOLOGY, WITH THE GOAL OF TRANSLATING FUNDAMENTAL FINDINGS INTO IMPROVED CARE OF PATIENTS. G PROTEIN-COUPLED RECEPTORS (GPCRS) ARE SOME OF THE MOST ESTABLISHED DRUG TARGETS. HOWEVER, THE CLINICAL SUCCESSES WITHIN THE GPCR SUPER-FAMILY ARE NOT EVENLY DISTRIBUTED. CERTAIN RECEPTOR FAMILIES HAVE MANY SUCCESSFUL DRUGS, SUCH AS ADRENERGIC GPCRS IN CARDIAC DISEASES AND DOPAMINE GPCRS IN PSYCHIATRIC DISEASES. OTHER GPCR FAMILIES, SUCH CHEMOKINE RECEPTORS, HAVE VERY FEW APPROVED DRUGS. I RECENTLY DISCOVERED A NEW GPCR SIGNALING PATHWAY THAT HAS RELEVANCE IN CHEMOKINE SIGNALING. THIS PATHWAY IS DIFFERENTIALLY REGULATED BY THE THREE CHEMOKINES THAT BIND TO CXCR3, WHICH IS EXPRESSED ON ACTIVATED T CELLS AND DRIVES TH1-MEDIATED INFLAMMATION IN THE SKIN AND OTHER TISSUES. THE GOAL OF MY PROJECT IS TO BIOCHEMICALLY DEFINE THIS NEW GPCR SIGNALING PATHWAY AND DISCOVER HOW THIS PATHWAY SIGNALS IN T CELLS. MY MENTOR, DR. ANDREW KRUSE, PROFESSOR OF BIOLOGICAL CHEMISTRY AND MOLECULAR PHARMACOLOGY, WAS ONE OF THE FIRST IN THE WORLD TO OBTAIN HIGH-RESOLUTION STRUCTURES OF GPCRS. HE HAS AN ESTABLISHED TRACK RECORD OF EXCELLENT TRAINEES AND LEADING DISCOVERIES. THROUGH THIS PROJECT, I WILL ACQUIRE CRITICAL SKILLS IN PROTEIN PURIFICATION AND STRUCTURAL BIOLOGY THAT I CURRENTLY LACK, BUT WHICH WILL BE INSTRUMENTAL IN ESTABLISHING MY OWN INDEPENDENT RESEARCH PROGRAM. THROUGH DR. KRUSE AND MY BROADER ADVISORY COMMITTEE, I WILL ALSO OBTAIN TRAINING IN SKILLS NECESSARY FOR MY INDEPENDENCE, INCLUDING WRITTEN AND ORAL COMMUNICATION, GRANT WRITING, LEADERSHIP AND MANAGEMENT, AND MENTORING/TEACHING. MY CLINICAL EXPERTISE IS IN AUTOIMMUNE SKIN AND CONNECTIVE TISSUE DISEASES AND IN THE EFFECTS OF IMMUNOMODULATORY MEDICATIONS. MANY OF THE DISEASES I TREAT APPEAR TO BE DRIVEN IN PART BY DYSFUNCTIONAL T CELL SIGNALING AS HIGHLIGHTED BY ABNORMAL CYTOKINE AND CHEMOKINE PROFILES. THE CHEMOKINES CXCL9, CXCL10, AND CXCL11 BIND TO THE CHEMOKINE RECEPTOR CXCR3. THESE, AND OTHER CHEMOKINES, ARE ABNORMALLY ALTERED IN DISEASES SUCH AS CUTANEOUS LUPUS AND PSORIASIS. MY RECENTLY PUBLISHED WORK AND PRELIMINARY DATA SHOW THAT CXCL9, CXCL10, AND CXCL11 CAUSE DIFFERENT POST-TRANSLATIONAL MODIFICATIONS ON CXCR3 AND LEAD TO DIVERGENT TRANSCRIPTIONAL RESPONSES. FURTHERMORE, CXCL11, BUT NEITHER CXCL9 NOR CXCL10, APPEARS TO SIGNAL THROUGH THIS NEW GPCR SIGNALING PATHWAY. THESE FINDINGS CHALLENGE THE CURRENT PARADIGM OF GPCR SIGNALING. I BELIEVE THAT THERAPEUTICALLY TARGETING CHEMOKINE RECEPTORS HAS BEEN CHALLENGING IN-PART BECAUSE WE ARE OVERLOOKING KEY INTRACELLULAR SIGNALING PATHWAYS THAT HAVE THERAPEUTIC RELEVANCE. I BELIEVE THIS PROJECT IS NOVEL, CHALLENGES ESTABLISHED PARADIGMS OF RECEPTOR SIGNALING, AND IS CLINICALLY SIGNIFICANT. UNDERSTANDING THE DIFFERENT CHEMOKINE SIGNALING PATHWAYS AT THE MOLECULAR LEVEL WILL HELP US DESIGN NEW THERAPEUTICS WITH THE DESIRED EFFECTS.