RM1HG011016

CENTER FOR GENOME IMAGING - PROJECT SUMMARY/ABSTRACT

CENTER FOR GENOME IMAGING (CGI) OBJECTIVES: THREE-DIMENSIONAL (3D) GENOME ORGANIZATION IS A MAJOR CONTRIBUTOR TO GENOME FUNCTION, AND YET, WE ARE ONLY AT THE VERY DAWN OF DISCOVERING THE STRUCTURAL SIGNATURES THAT UNDERLIE THAT ORGANIZATION.

THUS, THE GOAL OF THE PROPOSED STUDIES IS TO DEVELOP AND APPLY TOOLS THAT WILL ENABLE SEQUENCE-SPECIFIC IMAGING OF HUMAN GENOMES, IN THEIR ENTIRETY, WITH HIGH GENOMIC RESOLUTION. IN PARTICULAR, THE PROPOSED WORK WILL INNOVATE METHODS FOR FIXED AND LIVE CELL IMAGING USING DIFFRACTION-LIMITED LIGHT MICROSCOPY AND SUPER-RESOLUTION MICROSCOPY AS WELL AS DEVELOP NEW TOOLS FOR IMAGE ANALYSIS AND GENOME MODELING.

TO THIS END, IT WILL INVOLVE THE CONTINUED COLLABORATION OF FOUR LABORATORIES, WHOSE COLLECTIVE BREADTH OF EXPERTISE COVERS THE FIELDS OF CLASSICAL AND MOLECULAR GENETICS, CHROMOSOME DYNAMICS, IMAGING, HI-C ANALYSIS, CONVOLUTIONAL NEURAL NETWORKS, AND POLYMER PHYSICS-BASED AND RESTRAINT-BASED MODELING.

AN EQUALLY IMPORTANT OBJECTIVE OF THE PROPOSED STUDIES IS TO ENSURE A GENERATION OF RESEARCHERS WHOSE PERSONAL BREADTH OF EXPERTISE WILL COME TO MATCH THAT OF THE ENTIRE CURRENT TEAM.

HEALTH RELATEDNESS: WILL A SOLID GRASP OF 3D GENOME ORGANIZATION HAVE IMPLICATIONS FOR UNDERSTANDING HUMAN DEVELOPMENT? WILL IT CONTRIBUTE TO THE PROTECTION OF HUMAN HEALTH? WILL IT CONTRIBUTE TO STRATEGIES FOR EARLY DIAGNOSTICS AND PERHAPS EVEN THE DEVELOPMENT OF NEW THERAPIES? THE ANSWER TO ALL THESE QUESTIONS IS ALMOST CERTAINLY A RESOUNDING YES, AS KNOWLEDGE OF 3D GENOME ORGANIZATION WILL ENHANCE OUR CAPACITY TO ADDRESS BOTH FUNDAMENTAL BIOLOGICAL PROCESSES AS WELL AS DISEASE.

INNOVATION: AN ABUNDANCE OF STUDIES ARGUE THAT GENOMES FUNCTION AS INTEGRATED UNITS AND, YET, NO EXTANT TECHNOLOGIES ENABLE SEQUENCE-SPECIFIC IMAGING OF ENTIRE GENOMES AT HIGH GENOMIC RESOLUTION. THUS, THE CAPACITY OF RESEARCHERS TO FATHOM THE INTERPLAY BETWEEN 3D GENOME ORGANIZATION AND GENOME FUNCTION HAS BEEN LIMITED TO DISJOINTED SNAPSHOTS OF LOCALIZED EVENTS.

ACCORDINGLY, FIRST THREE AIMS WILL DEVELOP THE NEXT TIER OF TOOLS TO PUT ENTIRE GENOMES WITHIN REACH. THEY WILL ADVANCE A NEW METHOD, OLIGOFISSEQ, AND THEN INTEGRATE IT WITH OLIGOSTORM AND OLIGODNA-PAINT TO FINALLY ACHIEVE HIGH-THROUGHPUT IMAGING AT BOTH CONVENTIONAL AND SUPER-RESOLUTION. THEY WILL ALSO TACKLE TWO GENOMIC FEATURES THAT HAVE BEEN PROHIBITIVELY DIFFICULT TO CAPTURE – PRESENCE OF HOMOLOGS IN DIPLOID CELLS AND HIGHLY REPEATED SEQUENCES – AS WELL AS INNOVATE STRATEGIES FOR HIGH VOLUME DATA STORAGE, IMAGE PROCESSING AND ANALYSIS, AND MODELING.

FINALLY, A FOURTH AIM WILL IMPLEMENT METHODS FOR DISSEMINATING OUR TOOLS.

1. SCALING TECHNOLOGIES TOWARD WHOLE GENOME IMAGING

2. FILLING IN GAPS TO VISUALIZE CHROMOSOMES END-TO-END – TACKLING HOMOLOGS AND REPEATS

3. PROBE DESIGN, IMAGE ANALYSIS, MODELING, AND INTEGRATION OF EPIGENETIC DATA

4. TRAINING, RESOURCES, AND OPPORTUNITIES FOR ENGAGING COLLEAGUES IN WHOLE GENOME IMAGING

President And Fellows Of Harvard College

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Boston, Massachusetts 021155727 United States

Single Zip Code

Centers of Excellence in Genomic Science (RM1 Clinical Trials Optional) (PAR-19-204)

Amendment Since initial award the End Date has been extended from 03/31/26 to 03/31/27 and the total obligations have increased 275% from $3,248,226 to $12,168,228.