Project Grant R24OD035407

BUILDING A WIDE-FIELD, HIGH-RESOLUTION HISTOTOMOGRAPHY RESOURCE FOR BIOLOGY - EVERY LIVING ORGANISM IS MADE UP OF CELLS THAT ARE ORGANIZED INTO TISSUES, WHOSE MICRON-SCALE FEATURES DEFINE NORMALITY AND DISEASE. THESE PRINCIPLES INSPIRE THE LONG-TERM GOAL OF THIS PROJECT: TO ENABLE THE QUANTITATIVE CHARACTERIZATION OF THE GEOMETRY OF LIFE AND DISEASE AS A FOUNDATION FOR A COMPREHENSIVE AND INTEGRATIVE UNDERSTANDING OF HOW GENES, ENVIRONMENT AND DISEASE DETERMINE ANATOMICAL AND MICROANATOMICAL PHENOTYPES. IDEALLY, THE EFFECTS OF GENES AND ENVIRONMENT ON ANATOMICAL AND MICROANATOMICAL PHENOTYPES CAN BE ASSESSED ACROSS THE WHOLE ORGANISM. WE UNDERSTAND THE CELLULAR BASIS OF DISEASE AS A RESULT OF HISTOLOGY'S REPRESENTATION OF ALL CELL TYPES AND TWO CENTURIES OF APPLICATION TO CLINICAL MEDICINE. HOWEVER, HISTOLOGY IS 2-DIMENSIONAL, QUALITATIVE, SUBJECT TO SECTIONING ARTIFACT, AND SAMPLES ONLY ~1-2% OF SPECIMENS. TO FACILITATE ANATOMICALLY COMPREHENSIVE PHENOTYPING ACROSS WHOLE ORGANISMS, WE HAVE DEVELOPED A UNIQUE, STATE-OF-THE-ART 3D MODALITY (HISTOTOMOGRAPHY) BASED ON THE PRINCIPLES OF X-RAY TOMOGRAPHY AND THE CREATION OF LARGE-FIELD, HIGH RESOLUTION INSTRUMENTATION FOR TOMOGRAPHIC, SYNCHROTRON-BASED BEAMLINES. THE ABILITY TO CONDUCT HISTOLOGICAL ASSESSMENT IN A WHOLE ORGANISM IN 3 DIMENSIONS PROMISES REVOLUTIONARY ADVANCEMENTS ON NUMEROUS FRONTS. WE PROPOSE TO ESTABLISH THE GROUNDWORK FOR LARGE-SCALE ACCESS TO SYNCHROTRON MICROCT FOR BIOLOGY, INCLUDING A PILOT IMAGING FACILITY AT THE LAWRENCE BERKELEY NATIONAL LABORATORY (LBNL) AND THEN AT ARGONNE NATIONAL LABORATORY (ANL) FOR HISTOTOMOGRAPHY, TO INITIATE ACCESS TO VISUALIZATIONS AND HISTOTOMOGRAMS OF WHOLE, CENTIMETER-SCALE MODEL ORGANISMS AND TISSUES, AND TO ESTABLISH A BASIC SET OF WEB-BASED VISUALIZATION AND CROSS-REFERENCING TOOLS FOR THE SCIENTIFIC COMMUNITY. CLOUD-BASED DISSEMINATION OF RAW AND RECONSTRUCTED IMAGE DATA WILL BE PILOTED AT THE NATIONAL ENERGY RESEARCH SCIENTIFIC COMPUTING CENTER OPERATED BY LBNL OR ARGONNE LEADERSHIP COMPUTING FACILITY (ALCF) AT ANL, TO ENABLE USERS TO ADVANCE THEIR EDUCATIONAL, FUNCTIONAL, AND SCIENTIFIC GOALS. NOTABLY, THE PROPOSED GROUNDWORK WILL COMPRISE A FOUNDATION FOR COMPUTATIONAL PHENOTYPING THAT IS MORE COMPREHENSIVE, OBJECTIVE, PRECISE, AND STATISTICALLY VALIDATED. BROAD ACCESSIBILITY TO MICROANATOMICAL RESOURCES WOULD ENABLE VALUABLE, NEW MEANS OF MODEL VALIDATION, REPRODUCIBILITY, AND DISCOVERY, AND PROVIDE A NEW FOUNDATION FOR A MORE COMPREHENSIVE UNDERSTANDING OF GENETIC, MOLECULAR, AND CELLULAR FUNCTION IN THE STUDY OF NORMAL BIOLOGY AND DISEASE. WE EXPECT THE PROPOSED WORK TO LEAD TO UNEXPECTED RESEARCH OBSERVATIONS, IMPROVED CLINICAL OUTCOMES, ENHANCED ROBUSTNESS AND REPRODUCIBILITY OF BIOMEDICAL RESEARCH, AND ENHANCED SUSTAINABILITY AND HUMAN HEALTH BY ADVANCING THE QUALITY AND COMPREHENSIVENESS OF GLOBAL MONITORING OF ENVIRONMENTAL TOXICITY AND CLIMATE CHANGE.