Project Grant 2340865

CAREER: COMPUTATIONAL AND THEORETICAL INVESTIGATION OF ACTOMYOSIN CONTRACTION SYSTEMS -THE FUNCTION AND DEVELOPMENT OF ORGANISMS DEPENDS ON THE INCESSANT ACTIVITIES OF ITS CELLS. AS WE GROWTH FROM A SMALL EMBRYO, CELLS ARE CONSTANTLY GROWING, DIVIDING, MIGRATING, CHANGING SHAPES AND PULLING ON EACH OTHER. EVEN AS ADULTS, OUR CELLS CONTINUE THESE PROCESSES TO MAINTAIN BODY FUNCTIONS AND HEAL IN RESPONSE TO INJURY. ALL THESE ACTIVITIES RELY ON THE CELLS? ABILITY TO GENERATE AND TRANSMIT FORCES. THE ACTIN CYTOSKELETON, A MESHWORK OF SMALL, DYNAMIC FILAMENTS (ACTIN) AND MOLECULAR MOTORS THAT EXISTS INSIDE EACH CELL, IS THE MAIN DRIVER OF FORCE GENERATION AND PROPAGATION WITHIN CELLS AND ACROSS TISSUES AND ORGANS. ALL CELLS NEED A FUNCTIONAL ACTIN CYTOSKELETON TO MAINTAIN THEIR SHAPES, DIVIDE INTO NEW CELLS AND DRIVE MORPHOGENESIS DURING DEVELOPMENT. WITHOUT AN OPTIMALLY FUNCTIONING ACTIN CYTOSKELETON, CELLS? ABILITY TO MIGRATE, DIFFERENTIATE, DIVIDE AND RESPOND TO INJURY IS COMPROMISED, LEADING TO BIRTH DEFECTS, CANCERS, FIBROSIS, IMMUNODEFICIENCIES, ETC. TO FULLY UNDERSTAND THESE PROCESSES, WE NEED TO FIRST UNDERSTAND HOW THE ACTIN CYTOSKELETON WORKS AS A FUNCTION OF ITS COMPONENTS (MOTORS, FILAMENTS AND CROSSLINKERS), AND HOW IT GENERATES AND TRANSMITS FORCES WITHIN AND BETWEEN CELLS. ELUCIDATION OF THE ACTIN CYTOSKELETON?S ACTIVITIES FROM A MOLECULAR (BOTTOM UP) VIEW, IS IMPERATIVE IN ORDER TO PROVIDE A MECHANISTIC UNDERSTANDING OF ALL ITS ASSOCIATED CELL PROCESSES AND PROVIDE NEW THERAPEUTIC TARGETS RELATED TO CYTOSKELETAL DYSFUNCTION. EXPERIMENTAL CELL BIOLOGY AND IN VITRO STUDIES HAVE REVEALED MANY ASPECTS OF ACTIN CYTOSKELETON CONTRACTION, SUCH AS THE MOVEMENT OF MOLECULAR MOTORS, THE ACTIN AND MOTOR ORGANIZATION UNDERNEATH CELL MEMBRANES (THE CORTEX), AND THEIR ROLE DURING CELL DIVISION. HOWEVER, MANY IMPORTANT QUESTIONS THAT MUST BE ADDRESSED ARE EXTREMELY DIFFICULT, IF NOT IMPOSSIBLE, TO PROBE WITH EXPERIMENTS ALONE. THESE INCLUDE: 1) WHAT ARE THE MULTIPLE MECHANISMS THAT THE ACTIN CYTOSKELETON USE TO CONTRACT?; 2) WHAT MAKES ONE CONTRACTION MECHANISM DOMINANT OVER THE OTHERS?; 3) HOW MUCH FORCE CAN A NETWORK PRODUCE?; AND 4) HOW DO ADJACENT NETWORKS INTERACT? FORTUNATELY, THERE HAVE BEEN DRAMATIC RECENT IMPROVEMENTS IN COMPUTER POWER AND SIMULATION METHODOLOGIES THAT NOW ALLOW US TO CONDUCT IN SILICO, COMPUTATIONAL EXPERIMENTS THAT CIRCUMVENT WET LAB CONSTRAINTS, OPENING NOVEL WAYS TO PROBE AND UNCOVER HIDDEN ASPECTS OF ACTIN DYNAMICS NOT PREVIOUSLY ACCESSIBLE. THIS PROJECT TAKES ADVANTAGE OF THESE IMPROVEMENTS WITH A NOVEL, SYSTEMATIC SERIES OF THEORETICAL AND COMPUTATIONAL STUDIES OF CYTOSKELETAL DYNAMICS USING STATE-OF-THE-ART SIMULATION TECHNIQUES AND NEW APPROACHES DEVELOPED IN THE PRINCIPAL INVESTIGATOR LABORATORY. THIS PROJECT IS DIVIDED INTO TWO SCIENTIFIC TASKS THAT LEVERAGE OUR GROUP?S EXPERTISE IN PHYSICS. THE FIRST AIM IS TO MODEL ALL THREE MAIN ACTIN CONTRACTION MECHANISMS (FILAMENT BUCKLING, POLARITY SORTING, AND DEPOLYMERIZATION END-TRACKING) AND ASK UNDER WHICH CONDITIONS EACH BECOMES DOMINANT OVER THE OTHERS AND WHEN SYNERGISTIC AND ANTAGONISTIC EFFECTS ARISE. RESULTS FROM THIS TASK WILL SERVE AS A GUIDE TO DETERMINE THE UNDERLYING CONTRACTION MECHANISM IN DIFFERENT CELLS AND THE DEGREE TO WHICH DIFFERENT PERTURBATIONS WOULD ENHANCE OR IMPART ITS FUNCTION. IN THE SECOND AIM THE PRINCIPAL INVESTIGATOR WILL INVESTIGATE HOW MUCH FORCE ACTIN NETWORKS CAN PRODUCE, SUSTAIN OVER TIME, AND TRANSMIT TO ADJACENT NETWORKS. CURRENT STUDIES FOCUS MOSTLY ON CONTRACTION RATES, WHICH DOES NOT PROVIDE A SUFFICIENT PICTURE FOR THE LONG-TERM EFFECTS OF ACTIN CONTRACTION. THIS NEW APPROACH WILL HELP FILL THE GAP BETWEEN THE CYTOSKELETON?S INTERNAL DYNAMICS AND LARGE-SCALE CELL BEHAVIORS. IN ADDITION, THE PRINCIPAL INVESTIGATOR WILL ALSO IMPLEMENT AN EDUCATIONAL PLAN CONSISTING ACTIVITIES TARGETED TO DIFFERENT GROUPS: (I) A SUMMER WORKSHOP ON MODELLING CYTOSKELETAL SYSTEMS OPENED FOR THE WHOLE SCIENTIFIC COMMUNITY; (II) A SPECIAL TOPICS COURSE ON PHYSICS OF THE CYTOSKELETAL FOR SENIORS AND GRADUATE STUDENTS AT NORTH CAROLINA STATE UNIVERSITY; AND (III) A K-12 OUTREACH ACTIVITY TO TEACH STEM CONCEPTS USING ARCHERY. THESE THREE INTERRELATED TASKS ARE DESIGNED TO ADDRESS FUNDAMENTAL QUESTIONS OF HIGH RELEVANCE IN THE PHYSICS OF LIVING SYSTEMS. COMPLETION OF THESE TASKS WILL PROVIDE A SOLID THEORETICAL FOUNDATION OF THE INNER WORKINGS OF THE ACTIN CYTOSKELETON AND PAVE THE WAY FOR REALISTIC MODELS OF IN VIVO SYSTEMS, ALLOWING US TO STUDY ACTIN-ASSOCIATED CELLULAR PROCESSES AND DISEASES FROM A MECHANISTIC POINT OF VIEW. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.