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COLLABORATIVE RESEARCH: DMS/NIGMS 1: SIMULATING CELL MIGRATION WITH A MULTI-SCALE 3D MODEL FED BY INTRACELLULAR TENSION SENSING MEASUREMENTS -THIS IS A COLLABORATIVE PROJECT BETWEEN INDIANA UNIVERSITY INDIANAPOLIS AND PURDUE UNIVERSITY. CELL MIGRATION PLAYS A MAJOR ROLE IN MANY SETTINGS INCLUDING CANCER METASTASIS, WOUND HEALING, AND THE IMMUNE RESPONSE. FOR EXAMPLE, BREAST CANCER CELL MIGRATION IS CONSIDERED A MAJOR RISK FACTOR FOR METASTATIC BONE OR LUNG TUMORS AND FIBROBLAST MIGRATION IN WOUND HEALING HAS ROLES IN DIABETES AND NECROTIZING ENTEROCOLITIS (LIFE-THREATENING INTESTINAL WOUNDS THAT AFFECT 10% OF PREMATURE BABIES). THIS PROJECT AIMS TO UNDERSTAND THE INTRINSIC PROPERTIES OF CELL MIGRATION, I.E., HOW INTERNAL FORCES OF A CELL RESPOND TO THE PROPERTIES OF THE SURROUNDING, EXTERNAL ENVIRONMENT AND DRIVE CELL MIGRATION. TO DO THIS, THE PIS WILL DEVELOP A NOVEL MATHEMATICAL MODEL OF A MIGRATING CELL. THE MODEL COMBINES PRE-EXISTING KNOWLEDGE OF CELL MIGRATION AND CELL PROPERTIES WITH AN IMAGING METHOD THAT CAN MEASURE SUBCELLULAR FORCES. THE MODEL WILL YIELD FORCE INFORMATION THROUGHOUT THE CELL, NOT JUST AT THE MEASUREMENT LOCATIONS. ACCOMPANYING THAT MODEL WITH APPROPRIATE STATISTICAL ANALYSIS WILL HELP IDENTIFY HOW THE EXTERNAL ENVIRONMENT CAN EFFECT MIGRATION VIA INTERNAL SUBCELLULAR FORCE GENERATION. THIS, IN TURN, WILL HELP US BETTER UNDERSTAND HOW TO INHIBIT (E.G. CANCER) OR PROMOTE (E.G. WOUND HEALING) CELL MIGRATION IN ORDER TO IMPROVE PATIENT OUTCOMES. THE PROJECT WILL MENTOR AND TRAIN GRADUATES FROM MULTIPLE DISCIPLINES, UNDERGRADUATES FROM INSTITUTIONS LACKING RESEARCH OPPORTUNITIES THROUGH INDIANA UNIVERSITY INDIANAPOLIS?S NSF-DMS REU PROGRAM, AND SOCIOECONOMICALLY DISADVANTAGED HIGH SCHOOLERS THROUGH THE AMERICAN CHEMICAL SOCIETY PROJECT SEED/STEM. PLANS INCLUDE OUTREACH VIA PRESENTATIONS AND MINISYMPOSIA AT SEVERAL CONFERENCES, OPEN-ACCESS PUBLICATIONS, YOUTUBE POSTINGS, IN-CLASS MODULES, LOCAL COMMUNITY PRESENTATIONS (SCIENCE ON TAP), AND THE STEM YOUTH ENRICHMENT SUMMER PROGRAM FOR UNDERREPRESENTED HIGH SCHOOLERS. CELL MIGRATION IS DRIVEN BY ITS INTRACELLULAR FORCES BUT IS MAINLY DIRECTED BY EXTRACELLULAR PROPERTIES AND PERTURBATIONS. TO UNDERSTAND HOW EXTRACELLULAR PROPERTIES DETERMINE INTERNAL FORCES TO DIRECT CELL MIGRATION, THE PIS PLAN TO ACCOMPLISH THREE SPECIFIC AIMS: 1) DEVELOP A MODEL THAT INTEGRATES EXPERIMENTALLY MEASURED INTRACELLULAR TENSIONS AND USES THEM TO ESTABLISH A FORCE ARCHITECTURE THROUGHOUT THE CELL, 2) USE THAT MODEL AND THE EXPERIMENTAL MEASUREMENTS TO IDENTIFY WHICH SUBCELLULAR COMPONENTS PLAY MAJOR ROLES IN CELL MIGRATION, AND 3) USE MODELING AND EXPERIMENTS TO UNDERSTAND THE RESPONSE OF INTERNAL FORCES AND MIGRATION OF THE CELL TO THE EXTERNAL PROPERTIES. THROUGH THIS APPROACH THE PIS WILL BE ABLE TO IDENTIFY SEVERAL PRIMARY PATHWAYS (EXTERNAL PROPERTIES TO SUBCELLULAR COMPONENTS TO DIRECTED MOTION) BY WHICH EXTERNAL PROPERTIES USE SUBCELLULAR FORCES TO DIRECT MIGRATION. IN THE MODEL, THE CELL WILL BE REPRESENTED BY A SET OF INTERCONNECTED VISCOELASTIC SPRINGS MODELING THE MEMBRANE AND OTHER SUBCELLULAR COMPONENTS. THE FLOW WILL BE MODELED USING A NOVEL LATTICE-BOLTZMANN APPROACH FOR STEADY-STATE STOKES FLOW. FLUID-STRUCTURE INTERACTION WILL BE MODELED USING THE IMMERSED BOUNDARY METHOD. THE MODEL WILL BE CALIBRATED AND VALIDATED USING THE EXPERIMENTS. THE INTERNAL TENSION EXPERIMENTS WILL USE IMAGING METHODS AND VARIOUS MOLECULAR TENSION SENSORS TO CAPTURE THE FORCE LANDSCAPE WITHIN A CELL, PARTICULARLY AT FOCAL ADHESIONS, CYTOSKELETAL JUNCTURES, AND THE NUCLEAR ENVELOPE. THE EXTERNAL ENVIRONMENTAL ALTERATION WILL INCLUDE THE EXTRACELLULAR MATRIX STIFFNESS, CHEMOTACTIC GRADIENT, AND FLOW PROPERTIES. CORRELATION, SENSITIVITY, AND PRINCIPAL COMPONENT ANALYSES WILL BE USED TO IDENTIFY POTENTIAL MIGRATORY PATHWAYS. 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.
$200.0k 3/19/24