Project Grant R35GM152194

SYSTEMS AND NETWORK-LEVEL REGULATION OF CELL DEATH - PROJECT SUMMARY/ABSTRACT OUR LAB STUDIES MECHANISMS THAT CONTROL REGULATED CELL DEATH (RCD). RECENT STUDIES HAVE UNCOVERED THE EXISTENCE OF 15 DISTINCT FORMS OF RCD. THESE INCLUDE DIFFERENT FORMS OF APOPTOSIS, AND TWELVE MECHANISTICALLY DISTINCT FORMS OF REGULATED NECROSIS, INCLUDING FERROPTOSIS, NECROPTOSIS, OXEIPTOSIS, AND PARTHANATOS. IN GENERAL, RCD DESCRIBES SITUATIONS IN WHICH CELL DEATH RESULTS FROM THE USE OF SPECIFIC MECHANISMS TO SENSE STRESS, DEFINED SIGNALING CASCADES TO TRANSMIT INFORMATION, AND USE OF SPECIFIC EFFECTOR MOLECULES THAT DISMANTLE OR RUPTURE THE CELL. THUS, A KEY FEATURE OF ALL FORMS OF RCD IS THAT DEATH IS NOT AN INEVITABLE CONSEQUENCE OF OVERWHELMING STRESS, BUT RATHER, A DECISION WHICH IS PROACTIVELY MADE BY THE CELL. FOR MOST FORMS OF RCD, HOW THESE DECISIONS ARE MADE REMAINS UNCLEAR. OVER THE PAST FIVE YEARS, WE HAVE FOCUSED ON UNDERSTANDING HOW DIFFERENT FORMS OF DEATH ARE REGULATED AND IDENTIFYING FEATURES THAT CONTRIBUTE TO VARIATION IN CELL DEATH RESPONSES. OUR WORK HAS REVEALED THAT VARIATION IN CELL DEATH OUTCOMES IS OFTEN CAUSED BY INHIBITORY INTERACTIONS BETWEEN DIFFERENT CELL DEATH PATHWAYS. WHILE, OUR WORK CLEARLY DEMONSTRATES THAT DEATH PATHWAYS INHIBIT EACH OTHER PHENOTYPICALLY, MECHANISMS OF INTERACTION REMAIN UNCLEAR, LARGELY DUE TO OUR LIMITED UNDERSTANDING OF MOST FORMS OF REGULATED NECROSIS. OVER THE NEXT FIVE YEARS, WE AIM TO UNDERSTAND - WITH MECHANISTIC DETAIL - HOW DIFFERENT TYPES OF DEATH INTERACT, AND THE THERAPEUTIC IMPLICATIONS OF THESE INTERACTIONS. TO FACILITATE THESE EFFORTS, WE HAVE DEVELOPED NEW EXPERIMENTAL AND COMPUTATIONAL APPROACHES FOR STUDYING CELL DEATH, NEW GENETIC SCREENING APPROACHES FOR IDENTIFYING DEATH REGULATORY GENES, AND NEW COMPUTATIONAL TOOLS FOR INFERRING THE ACTIVATION DYNAMICS AND CIRCUITRY OF DEATH REGULATORY PROCESSES. COMBINED, THESE NEW METHODS ALLOW US TO STUDY EVERY CELL DEATH PATHWAY, EACH WITH EQUAL PRECISION AND SENSITIVITY, AND WITH UNPRECEDENTED EASE AND THROUGHPUT. USING THESE METHODS, WE WILL IDENTIFY MECHANISMS OF REGULATION AND MECHANISMS OF COORDINATION BETWEEN APOPTOTIC AND NON-APOPTOTIC FORMS OF DEATH. WE WILL EXPLORE THE IMPLICATIONS OF INTERACTIONS BETWEEN DEATH PATHWAYS ON THE EFFICACY OF COMBINATION DRUG THERAPIES. FINALLY, WE WILL CHARACTERIZE UNEXPECTED DEATH REGULATORY PATHWAYS THAT WE HAVE IDENTIFIED IN THE CONTEXT OF DYSREGULATED GENE EXPRESSION. OUR VISION IS THAT OUR DEEP INSIGHTS INTO THE MECHANISMS OF RCD WILL HAVE IMMEDIATE THERAPEUTIC IMPLICATIONS FOR DISEASES LIKE CANCER, WHERE THERAPIES NEED TO KILL CANCER CELLS WITH SELECTIVITY AND PRECISION. TO FACILITATE THIS VISION, OUR APPROACH IS TO STUDY CELL DEATH IN NORMAL AND CANCER CELLS, IN THE CONTEXT OF DRUG THERAPY. ADDITIONALLY, TO IMPROVE OUR ABILITY TO TRANSLATE OUR FINDINGS TO OTHER RELEVANT CONTEXTS, WE STUDY CELL DEATH ACROSS VARIED ENVIRONMENTAL AND GENETIC CONTEXTS, AND WE USE MATHEMATICAL MODELING AND BIOINFORMATIC ANALYSES TO IDENTIFY FEATURES THAT ARE PREDICTIVE OF THE OBSERVED PHENOTYPES.