VANDERBILT UNIVERSITY

PROTECT AGAINST EMERGENT ALPHAVIRUSES THROUGH COMPUTATION (PEAC) - ALPHAVIRUSES CAUSE NEUROLOGICAL AND RHEUMATIC DISEASES AND POSE SUBSTANTIAL RISKS TO HUMAN HEALTH THROUGH RECURRING NATURAL OUTBREAKS, EPIDEMICS, AND THE THREAT OF BIOTERRORISM. SOME ALPHAVIRUSES (E.G., EASTERN EQUINE ENCEPHALITIS VIRUS AND WESTERN EQUINE ENCEPHALITIS VIRUS) ARE ENDEMIC IN THE UNITED STATES, WHEREAS OTHERS HAVE ONLY RECENTLY EMERGED DOMESTICALLY. ALPHAVIRUSES ARE TRANSMITTED THROUGH MOSQUITOES, AND MULTIPLE FACTORS CONTRIBUTE TO THEIR EMERGENCE AND RE-EMERGENCE, INCLUDING CLIMATE CHANGE, URBANIZATION, AND TRAVEL. THE SINGLE APPROVED VACCINE AGAINST ALPHAVIRUSES, IXCHIQ, INDUCES ONLY SPECIES-SPECIFIC PROTECTION AGAINST CHIKUNGUNYA VIRUS. HOWEVER, MULTIPLE CROSS-REACTIVE PAN-ALPHAVIRUS ANTIBODIES THAT CAN PROTECT MICE AGAINST INFECTION BY A RANGE OF ALPHAVIRUSES HAVE BEEN IDENTIFIED BY MEMBERS OF OUR CONSORTIUM, PROVIDING TEMPLATES FOR VACCINE DESIGN. TO DEVELOP BROADLY PROTECTIVE VACCINES, WE PROPOSE CREATING HETERO-NANOPARTICLES THAT CO-PRESENT IMMUNOGENS CAPABLE OF INDUCING BROADLY PROTECTIVE ANTIBODIES AGAINST THE TWO COMPLEXES OF ALPHAVIRUSES, NAMELY ENCEPHALITIC VIRUSES AND ARTHRITOGENIC VIRUSES. DURABILITY OF THE IMMUNOGEN WILL BE ENHANCED USING AN INNOVATIVE APPROACH TO IMPROVE IN VIVO TRAFFICKING. WE WILL FURTHER COMBINE THIS B-CELL TARGETING DUAL-IMMUNOGEN WITH A BROAD T-CELL IMMUNOGEN COVERING ALL ALPHAVIRUSES. BOTH B AND T CELL IMMUNOGENS WILL BE DESIGNED USING NOVEL ARTIFICIAL INTELLIGENCE/MACHINE LEARNING (AI/ML)-BASED METHODS THAT IMPROVE UPON PREVIOUS APPROACHES IN TERMS OF THERMOSTABILIZATION, EPITOPE-FOCUSING, EPITOPE-SCAFFOLDING, GERMLINE-TARGETING, IMMUNOGENIC T CELL EPITOPE SELECTION AND T CELL EPITOPE IMMUNOGEN DESIGN. WE WILL COMBINE PREVIOUSLY PUBLISHED AI/ML TOOLS WITH OUR OWN ALGORITHMS AND TRAIN NEW NEURAL NETWORKS, WHEN NECESSARY, TO DEVELOP A ROBUST COMPUTATIONAL IMMUNOGEN DESIGN PIPELINE. WE WILL EXTENSIVELY TEST ALL IMMUNOGENS IN VITRO AND IN VIVO USING TRANSGENIC ATX-GK MICE, WHICH CARRY A FULLY HUMAN IG REPERTOIRE, THEREBY MORE CLOSELY MIMICKING THE HUMAN ANTIBODY-RESPONSE. DEEP ANALYSIS OF B-CELL RESPONSES BY SINGLE-CELL BCR SEQUENCING WILL COMPLEMENT SEROLOGICAL ASSAYS TO ITERATIVELY IMPROVE THE IMMUNOGENS. THE BEST IMMUNOGENS WILL BE VALIDATED AS PART OF IMMUNIZATION AND CHALLENGE STUDIES IN NON-HUMAN PRIMATE MODELS OF ALPHAVIRUS PATHOGENESIS. WE WILL EMPLOY THE MOST ADVANCED IN SILICO AND IN VITRO TECHNIQUES TO STRUCTURALLY CHARACTERIZE THE ALPHAVIRUS GENUS AND PROVIDE PUBLIC ACCESS TO A CURATED DATABASE FOR STRUCTURES OF VIRAL PROTEINS, RECEPTORS, ANTIBODIES AND POST-TRANSLATIONAL MODIFICATIONS. METHODS WILL INCLUDE COMPUTATIONAL PREDICTIONS (I.E., PROTEIN STRUCTURES, INTERACTIONS, AND MODIFICATIONS) AND EXPERIMENTAL VALIDATION USING EM POLYCLONAL EPITOPE MAPPING (EMPEM), HIGH-THROUGHPUT CRYO-ELECTRON MICROSCOPY, X-RAY CRYSTALLOGRAPHY AND MASS SPECTROMETRY. THIS EXTENSIVE DATASET WILL ALSO BE USED TO REFINE OUR AI/ML ALGORITHMS. THE BEST IMMUNOGEN WILL BE TESTED IN A PHASE I, FIRST-IN-HUMAN CLINICAL TRIAL BY THE VANDERBILT VACCINE RESEARCH PROGRAM, IN PARTNERSHIPS WITH MODERNA INC., KCASBIO, AND THE VANDERBILT COORDINATING CENTER. THE PROPOSED DESIGN IS A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLINDED STUDY TO ASSESS THE SAFETY AND IMMUNOGENICITY OF THE SELECTED VACCINE CANDIDATE. THE PRIMARY OBJECTIVE OF THE PHASE I STUDY WILL BE SAFETY AND REACTOGENICITY. SECONDARY OBJECTIVES WILL ALSO INCLUDE EVALUATION OF IMMUNOGENICITY, INCLUDING THE POTENCY AND DURABILITY OF SERUM ANTIBODY RESPONSES. THE PROPOSED WORK WILL COMBINE AND IMPROVE THE MOST ADVANCED TECHNOLOGIES IN COMPUTATIONAL BIOLOGY, STRUCTURAL BIOLOGY, VACCINOLOGY, VIROLOGY AND IMMUNOLOGY TO STUDY AND UNDERSTAND ALPHAVIRUS INFECTION AND ITS INTERACTIONS WITH THE HOST IMMUNE SYSTEM. WE WILL LEVERAGE THIS INFORMATION TO DEVELOP A BROAD ALPHAVIRUS VACCINE. OUR GOAL IS TO PROTECT AGAINST EMERGENT ALPHAVIRUSES THROUGH COMPUTATION (PEAC).

NSF I-CORPS HUB (TRACK 1): MID-SOUTH REGION -THE BROADER IMPACT/COMMERCIAL POTENTIAL OF THIS NSF I-CORPS HUBS PROJECT IS THE DEVELOPMENT OF A SUSTAINABLE, INCLUSIVE, INNOVATION ECOSYSTEM THAT WILL IMPART SHARED ECONOMIC PROSPERITY ACROSS THE US MID-SOUTH REGION. THE MID-SOUTH HUB?S FORMATIVE, EVIDENCE-DRIVEN APPROACH MAY INFORM HOW INCLUSIVE INNOVATION ECOSYSTEMS CAN BE ESTABLISHED IN REGIONS WITH NASCENT ECONOMIC ACTIVITY. THIS KNOWLEDGE WILL AUGMENT TEAM PREPARATION, MAXIMIZING THE VALUE EXTRACTED FROM I-CORPS TRAINING. THE HUB WILL FURTHER AMPLIFY THE DOWNSTREAM SUCCESSES AND SUSTAINABILITY OF DEEP TECHNOLOGY VENTURES, INCLUDING GRANT ACQUISITION, FUNDRAISING, SUSTAINABLE REVENUES, AND NET-POSITIVE LIQUIDITY EVENTS. SUCCESS WILL BE LEVERAGED TO INFLUENCE INNOVATION CULTURE AT REGIONAL INSTITUTIONS, LEADING TO THE INCENTIVIZATION OF ENTERPRISING FACULTY, STUDENTS, AND STAFF. THE DIVERSE LEADERSHIP TEAM AND INCLUSIVE BENCH OF INSTRUCTORS WILL INCREASE THE HUB?S ABILITY TO CONNECT TO INNOVATORS AND MENTORS OF ALL BACKGROUNDS, INCLUDING THOSE WHO ARE DISADVANTAGED OR UNDERREPRESENTED. THESE EFFORTS WILL INCLUDE BUILDING COMMERCIALIZATION CAPACITY AT UNDERREPRESENTED INSTITUTIONS. EVIDENCE FROM THE DELIBERATE IMPLEMENTATION OF A DEMOCRATIZED ORGANIZATIONAL STRUCTURE WILL BE EVALUATED FOR ITS CAPABILITY TO ENCOURAGE AND PRESERVE THE COGNITIVE PROXIMITY OF ECOSYSTEM MEMBERS. THIS KNOWLEDGE WILL BE DISSEMINATED VIA THE NATIONAL INNOVATION NETWORK TO DRIVE TRANSLATIONAL IMPACTS AND ECONOMIC DEVELOPMENT, SHAPING THE FUTURE OF AMERICAN INNOVATION. THIS I-CORPS HUBS PROJECT IS BASED ON THE DEVELOPMENT OF A USE-INSPIRED INCUBATOR THAT USES DATA-DRIVEN APPROACHES TO DEVELOP BEST PRACTICES, INFLUENCE ECONOMIC POLICY, INSPIRE ADOPTION OF INCLUSIVE APPROACHES TO INNOVATION, AND INSTRUCT FUTURE PROGRAMMATIC INVESTMENTS. CURRENTLY, A GAP EXISTS IN UNDERSTANDING HOW REGIONAL INNOVATION CLUSTERS CAN UNIFY TO DRIVE THE DEVELOPMENT OF A PROLIFIC INNOVATION ECOSYSTEM. ADDRESSING THIS GAP WILL ENABLE POLICYMAKERS AND GOVERNMENT AGENCIES TO IMPLEMENT EVIDENCE-BASED APPROACHES TO INFORM PROGRAMMATIC INVESTMENTS AND MAXIMIZE TECHNOLOGY COMMERCIALIZATION, ECONOMIC DEVELOPMENT, AND OVERALL NATIONAL INNOVATION READINESS. THIS CONSORTIUM OF DIVERSE, DEEP TECHNOLOGY-PRODUCING INSTITUTIONS FROM DISPARATE LOCATIONS WITHIN THE MID-SOUTH REGION WILL LEVERAGE THE I-CORPS PROGRAM TO CATALYZE TECHNOLOGICAL COMMERCIALIZATION, SPUR ECONOMIC DEVELOPMENT, AND INFORM THE FUTURE OF INCLUSIVE AMERICAN INNOVATION. THE HUB WILL PRIORITIZE A FORMATIVE, LONGITUDINAL ASSESSMENT TO ITERATIVELY OPTIMIZE KEY ACTIVITIES, INCLUDING TEAM RECRUITMENT, REGIONAL AND NATIONAL I-CORPS TRAINING, UPSTREAM CHANGES IN UNIVERSITY INNOVATION CULTURE, DOWNSTREAM IMPACTS ON SUCCESSFUL COMMERCIALIZATION, AND AN INCLUSIVE INNOVATION CORRIDOR ACROSS THE MID-SOUTH. THIS EFFORT WILL ADVANCE TECHNOLOGY TRANSFER FROM ACADEMIC INSTITUTIONS INTO ENTREPRENEURIAL VENTURES THAT SEED EMERGENT, REGIONAL ECOSYSTEMS. THE DATA-DRIVEN, PERFORMANCE IMPROVEMENT APPROACH WILL ENSURE BEST PRACTICES ARE EVIDENCE-BASED AND CREATE A MODEL FOR OTHER REGIONS SEEKING TO INDUCE INCLUSIVE INNOVATION CLUSTER DEVELOPMENT. 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.

EXPANDING AND SCALING THE PYRAMID MODEL IN PRE-KINDERGARTEN AND KINDERGARTEN CLASSROOMS IN DISTRICTS ACROSS THE U.S.

GRANT PROGRAM

EXRNA IN COLORECTAL CARCINOMA: BIOGENESIS AND FUNCTION

CONTRACTOR SHALL CONDUCT THE RESEARCH EFFORT "META TOOLS EXTENSION AND MATURATION".

6/6 HBCD PRENATAL EXPERIENCES AND LONGITUDINAL DEVELOPMENT (PRELUDE) CONSORTIUM VANDERBILT - PROJECT SUMMARY/ABSTRACT BRAIN DEVELOPMENT OCCURS AT A RAPID PACE PRENATALLY AND THROUGHOUT CHILDHOOD, IMPACTED BY DYNAMIC GENETIC AND ENVIRONMENTAL INFLUENCES. STUDIES USING ADVANCED NEUROIMAGING HAVE PROVIDED SIGNIFICANT INSIGHTS INTO BRAIN DEVELOPMENT BUT HAVE BEEN LIMITED BY SMALL SAMPLE SIZE, ESPECIALLY FOR HIGH-RISK POPULATIONS. SUBSTANCE- EXPOSED INFANTS ARE AT PARTICULARLY HIGH RISK FOR ADVERSE OUTCOMES; HOWEVER, FINDINGS ARE INCONSISTENT, MAKING IT DIFFICULT TO DISENTANGLE PRENATAL EXPOSURE EFFECTS FROM OTHER ADVERSE INFLUENCES. THE OBJECTIVES OF OUR HEALTHY BRAIN AND CHILD DEVELOPMENT (HBCD) PRENATAL EXPERIENCES AND LONGITUDINAL DEVELOPMENT (PRELUDE) CONSORTIUM ARE TO CHARACTERIZE TYPICAL TRAJECTORIES OF BRAIN DEVELOPMENT FROM BIRTH THROUGH CHILDHOOD, MEASURING THE INFLUENCE OF KEY BIOLOGIC AND ENVIRONMENTAL FACTORS AND THEIR INTERACTIONS ON CHILD SOCIAL, COGNITIVE, AND EMOTIONAL DEVELOPMENT. WE WILL ASSESS HOW CHILDREN PRENATALLY EXPOSED TO OPIOIDS AND OTHER SUBSTANCES, AS WELL AS ENVIRONMENTAL ADVERSITY, DIFFER IN THOSE BRAIN TRAJECTORIES AND OUTCOMES. OUR CONSORTIUM CONSISTS OF SIX CENTERS (ARKANSAS CHILDREN’S RESEARCH INSTITUTE, CASE WESTERN RESERVE UNIVERSITY, CINCINNATI CHILDREN’S HOSPITAL, CHILDREN’S NATIONAL MEDICAL CENTER, UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, AND VANDERBILT UNIVERSITY) WHICH HAVE COLLABORATED PREVIOUSLY AND HAVE COMPLEMENTARY EXPERTISE IN NEUROIMAGING, NEUROPHYSIOLOGY, LONGITUDINAL CLINICAL RESEARCH, CHILD DEVELOPMENT, SUBSTANCE EXPOSURE AND ADDICTION, ETHICAL/LEGAL ISSUES, AND CLINICAL CARE OF HIGH-RISK INFANTS/CHILDREN. THE PRELUDE CONSORTIUM WILL RECRUIT 680 PREGNANT WOMEN WITH SUBSTANCE USE, 680 AT-RISK PREGNANT WOMEN WITHOUT SUBSTANCE USE, AND 1360 COMPARISON PREGNANT WOMEN REPRESENTATIVE OF THE GENERAL POPULATION TO CONTRIBUTE TO THE OVERALL HBCD STUDY. WE WILL WORK CLOSELY WITH THE OTHER SITES, THE HBCD CONSORTIUM ADMINISTRATIVE CORE, AND THE HBCD DATA COORDINATING CENTER TO DEVELOP A COMPREHENSIVE STUDY PROTOCOL AND ENSURE COMPLIANCE OF STUDY WORKFLOW AND DATA TRANSFER. OUR CONSORTIUM HAS AN OPTIMIZED RESEARCH PROTOCOL AND 4 SPECIFIC AIMS: 1) EMPLOY ETHICAL AND EVIDENCE-BASED BEST PRACTICES TO ENROLL AND RETAIN A DIVERSE COHORT OF PREGNANT WOMEN INTO A LONGITUDINAL STUDY OF INFANT/CHILD BRAIN DEVELOPMENT, OVERSAMPLING MOTHERS FROM HIGH-RISK BACKGROUNDS AND THOSE USING SUBSTANCES DURING PREGNANCY; 2) ENGAGE A COMPREHENSIVE ARRAY OF MATERNAL- AND CHILD-ORIENTED COMMUNITY STAKEHOLDERS TO IDENTIFY COMMUNITY CONCERNS AND PRIORITIES REGARDING THIS RESEARCH, MINIMIZE RISKS, AND PROMOTE LONG-TERM ENGAGEMENT OF THE RECRUITED CHILD-MOTHER DYADS; 3) COLLECT RICH DATA TO EXAMINE HOW MATERNAL HEALTH CONTEXT AND BROADER ENVIRONMENTAL FACTORS MAY AFFECT THE MATERNAL-FETAL DYAD AND NEURODEVELOPMENT OF CHILDREN; 4) CAPTURE KEY DEVELOPMENTAL WINDOWS DURING WHICH MATERNAL AND ENVIRONMENTAL FACTORS MAY INTERACT WITH BRAIN AND BEHAVIORAL DEVELOPMENT OF CHILDREN. THE INSIGHTS FROM THESE DATA WILL PROVIDE GREATER UNDERSTANDING OF FACTORS AFFECTING EARLY CHILDHOOD BRAIN DEVELOPMENT, ALLOWING TARGETED INTERVENTIONS AND IMPROVED OUTCOMES FOR MOTHER-CHILD DYADS.

ASSURANCEBASED LEARNING-ENABLED CYBER-PHYSICAL SYSTEMS (ALC)

THIS PROJECT AIMS TO CREATE A FULL SET OF MODULAR TOOLS FOR AUTONOMOUS ROBOTIC SURGERY AS WELL AS THE PERCEPTUAL CAPABILITIES AND LOGICAL FRAMEWORK TO INTEGRATE THEM INTO FULL PROCEDURES. THE TEAM HAS DIVIDED SURGICAL PROCEDURES INTO SEVEN CORE TASKS RETRACTION RESECTION HEMOSTASIS PROPRIOCEPTION DEBRIDEMENT PALPATION AND SUTURING. THE TEAM THEN CREATES A LOGICAL FRAMEWORK THAT DEFINES PROCEDURES IN TERMS OF THESE SEVEN BASIC TASKS AND ALLOWS THE ROBOT TO PROGRESS FROM ONE TASK TO ANOTHER. AS THE ROBOT CARRIES OUT A PROCEDURE IT NOT ONLY ASSESSES COMPLETENESS OF THE SUBTASK BUT ALSO ITS OWN UNCERTAINTY ALLOWING IT TO REQUEST HUMAN SURGEON INTERVENTION WHEN UNCERTAINTY IS HIGH. THE PROGRAM CULMINATES WITH TWO DEMONSTRATIONS OF AUTONOMOUS ROBOTIC SURGERY.

THE CONSORTIUM FOR RISK EVALUATION WITH STAKEHOLDER PARTICIPATION (CRESP IV) COOPERATIVE AGREEMENT WILL ADVANCE COST-EFFECTIVE, RISK-INFORMED CLEANUP OF THE NATION'S NUCLEAR WEAPONS PRODUCTION FACILITY WASTE SITES AND COST-EFFECTIVE, RISK-INFORMED MANAGEMENT OF LEGACY DEFENSE AND ENERGY NUCLEAR WASTES AND POTENTIAL FUTURE NUCLEAR SITES AND WASTES. THIS MISSION WILL BE ACCOMPLISHED BY SEEKING TO IMPROVE THE SCIENTIFIC AND TECHNICAL BASIS FOR ENVIRONMENTAL MANAGEMENT DECISIONS TO BE MADE BY THE DOE AND BY FOSTERING PUBLIC PARTICIPATION IN THAT SEARCH.

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) -THE NATIONAL SCIENCE FOUNDATION (NSF) GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) IS A HIGHLY COMPETITIVE, FEDERAL FELLOWSHIP PROGRAM. GRFP HELPS ENSURE THE VITALITY AND DIVERSITY OF THE SCIENTIFIC AND ENGINEERING WORKFORCE OF THE UNITED STATES. THE PROGRAM RECOGNIZES AND SUPPORTS OUTSTANDING GRADUATE STUDENTS WHO ARE PURSUING RESEARCH-BASED MASTER'S AND DOCTORAL DEGREES IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS (STEM) AND IN STEM EDUCATION. THE GRFP PROVIDES THREE YEARS OF FINANCIAL SUPPORT FOR THE GRADUATE EDUCATION OF INDIVIDUALS WHO HAVE DEMONSTRATED THEIR POTENTIAL FOR SIGNIFICANT RESEARCH ACHIEVEMENTS IN STEM AND STEM EDUCATION. THIS AWARD SUPPORTS THE NSF GRADUATE FELLOWS PURSUING GRADUATE EDUCATION AT THIS GRFP INSTITUTION. 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.

VANDERBILT UNIVERSITY BIOMOLECULAR MULTIMODAL IMAGING CENTER FOR 3-DIMENSIONAL MAPPING OF THE HUMAN KIDNEY - PROJECT SUMMARY – OVERALL THIS APPLICATION PROPOSES THE CONTINUATION OF A TISSUE MAPPING CENTER (TMC) FOR THE HUMAN KIDNEY WITHIN THE HUMAN BIOMOLECULAR ATLAS PROGRAM (HUBMAP). THE MISSION OF THE PROPOSED TMC IS TO BUILD A PLATFORM OF INTEGRATED TECHNOLOGIES FOR IMAGING AND MOLECULAR ANALYSIS THAT ENABLES THE CONSTRUCTION OF COMPREHENSIVE 3- DIMENSIONAL MOLECULAR ATLASES OF THE HUMAN KIDNEY. THIS TMC WILL LEVERAGE THE UNIQUE RESOURCES OF THE MASS SPECTROMETRY RESEARCH CENTER AND THE NATIONAL RESEARCH RESOURCE FOR IMAGING MASS SPECTROMETRY AT VANDERBILT UNIVERSITY, THE WORLD-CLASS CLINICAL ENVIRONMENT OF THE VANDERBILT UNIVERSITY MEDICAL CENTER, AND THE ADVANCED BIOCOMPUTATIONAL INFRASTRUCTURE AVAILABLE TO THE TMC THROUGH THE DATA ANALYSIS CORE LABORATORIES AT VANDERBILT UNIVERSITY AND THE DELFT UNIVERSITY OF TECHNOLOGY, NETHERLANDS TO CREATE A CAPABILITY TO MOLECULARLY CHARACTERIZE HUMAN TISSUES IN 3-DIMENSIONS AT A LEVEL OF UNDERSTANDING UNRIVALED BY CURRENT TECHNOLOGIES. THE INNOVATIVE ASPECT OF THE PROPOSED TMC IS THE INTEGRATION OF IMAGING MASS SPECTROMETRY, HIGHLY MULTIPLEXED IMMUNOFLUORESCENCE MICROSCOPY, AUTOFLUORESCENCE MICROSCOPY, STAINED MICROSCOPY, SPATIAL TRANSCRIPTOMICS, SPATIAL PROTEOMICS, AND SINGLE-CELL RNA-SEQ TO CREATE COMPREHENSIVE 2-D AND 3-D MOLECULAR AND CELLULAR ATLASES OF THE HUMAN KIDNEY. THROUGH SEGMENTATION AND CELL TYPE ANALYSIS DETERMINED BY CLASSICAL MARKERS, WE WILL CORRELATE OUR MOLECULAR AND CLINICAL INFORMATION TO THE EXISTING KNOWLEDGE OF THE KIDNEY TO BETTER DEFINE THE NORMAL PHENOTYPES ACROSS A RANGE OF DIVERSE SAMPLES. THE APPLICATION OF THIS MULTIMODAL PIPELINE TO THE KIDNEY WILL PROVIDE A NEW PARADIGM OF UNDERSTANDING THE NORMAL STATE OF THIS ORGAN ACROSS MULTIPLE DIMENSIONS, BOTH MOLECULAR (E.G., LIPIDS, METABOLITES, PROTEINS, AND TRANSCRIPTS) AND SPATIAL (E.G., WHOLE ORGANS TO SINGLE CELLS). AS A HUBMAP PARTICIPANT, THE MOLECULAR ATLASES PRODUCED BY THIS TMC WILL BE DISSEMINATED TO THE COMMUNITY AND TO COLLABORATORS TO GENERATE NEW HYPOTHESES REGARDING THE FUNCTION OF THIS IMPORTANT ORGAN SYSTEM, ENABLING NEW INSIGHT INTO HUMAN HEALTH AND DISEASE. THIS MULTIDISCIPLINARY EFFORT REQUIRES THE CREATION AND INTEGRATION OF THREE CAPABILITIES TO 1) PROCURE AND MANAGE HUMAN TISSUE SPECIMENS, 2) DETERMINE AND MITIGATE NON-BIOLOGICAL PRE- ANALYTICAL FACTORS, AND 3) ACQUIRE, PROCESS, AND DISSEMINATE MULTIMODAL 3-DIMENSIONAL IMAGING AND LARGE-SCALE OMICS DATA. THE GOAL OF THE PROPOSED KIDNEY TMC IS TO CREATE ATLASES FOR COMMUNITY USERS, PHYSICIANS, AND RESEARCHERS TO NAVIGATE ACROSS THE ANATOMICAL AND MOLECULAR LANDSCAPE OF THE KIDNEY, GENERATE NOVEL HYPOTHESES, AND TACKLE MEANINGFUL BIOMEDICAL RESEARCH QUESTIONS.

NATIONAL CENTER FOR LEADERSHIP IN INTENSIVE INTERVENTION 2 (NCLII-2)

REGULATION OF CYTOKINESIS

BUILD AN F6 MODEL-DRIVEN DEVELOPMENT KIT (F6MDK), A MODEL-BASED DEVELOPMENT ENVIRONMENT AND A RUN-TIME SYSTEM FOR F6 MIDDLEWARE, USING AN INTEGRATION OF EXISTING SOLUTIONS AND NEW DESIGNS, WITH A SET OF NOVEL SOFTWARE IMPLEMENTATIONS.

DISSECTING THE MECHANISMS OF REGULATION AND QUALITY CONTROL IN RIBOSOME ASSEMBLY AND THE CONSEQUENCES OF THEIR FAILURE

MECHANISM OF WNT SIGNAL TRANSDUCTION

ASSURED NEURO-SYMBOLIC COMPONENTS AND SYSTEMS (ANSCS)

IRIS CENTER

VANDERBILT AUD RESEARCH AND EDUCATION CENTER (VAREC) - ABSTRACT THE CENTRAL THESIS OF THE VANDERBILT AUD RESEARCH AND EDUCATION CENTER (VAREC) IS THAT EFFECTIVE TREATMENT REQUIRES RECOGNITION OF, AND DEEP UNDERSTANDING OF THE DIVERSE SYMPTOMS, ETIOLOGIES, AND DISEASE PROGRESSIONS THAT UNDERLIE WHAT IS UNITARILY REFERRED TO AS ALCOHOL USE DISORDER (AUD). WE PROPOSE A REVERSE TRANSLATIONAL “PRECISION NEUROSCIENCE” APPROACH. WE WILL DISSECT AUD ENDOPHENOTYPES TO GENERATE HUMAN CIRCUIT CONSTRUCT VALIDATED ANIMAL MODELS THAT WE WILL UTILIZE TO GAIN MECHANISTIC INSIGHTS AND TEST THERAPEUTIC TARGETS. VAREC WILL CONSIST OF 4 RESEARCH COMPONENTS (PROJECTS1-4) SUPPORTED BY ADMINISTRATIVE AND RESEARCH CORES, AS WELL AS A DISSEMINATION CORE. PROJECT 1 (BLACKFORD) EXPANDS OUR INITIAL HUMAN IMAGING STUDIES INTO A DEEP SAMPLING APPROACH TO ANALYZE BNST AND NETWORK CONNECTIVITY IN AUD ACROSS THE ABSTINENCE TIMESPAN, EXPLORING INDIVIDUAL DIFFERENCES IN THESE NETWORKS WITH AUD RELEVANT DOMAINS SUCH AS ANXIETY AND DEPRESSION. PROJECT 2 (WINDER) WILL BUILD OFF AN ALREADY ACTIVE COLLABORATION WITH PROJECT 1 TO PERFORM REVERSE TRANSLATIONAL MOUSE STUDIES TO TEST EMERGENT HYPOTHESES ON INSULA-BNST AND HIPPOCAMPAL-BNST CONNECTIVITY IN MOUSE MODELS OF AUD, AND TO EXPLORE POTENTIAL TIME-DEPENDENT THERAPEUTIC APPROACHES DURING ABSTINENCE. PROJECT 2 WILL ALSO PERFORM SPECIFIC BROAD-SCALE MOUSE BRAIN IMAGING STUDIES TO DEFINE NETWORK NODES FOR PROJECT 1 TO EXPLORE IN YEARS 4-5. PROJECT 3 (CALIPARI) WILL EXPLORE WHETHER ALTERATIONS IN NEGATIVE AFFECT OBSERVED IN PROJECT 1 AND PROJECT 2 LEAD DIRECTLY TO FUNCTIONAL ENHANCEMENT OF NEGATIVE REINFORCEMENT-ORIENTED CIRCUITRIES AND BEHAVIOR. FINALLY, PROJECT 4 (SICILIANO) WILL ENGAGE IN DEEP PHENOTYPING OF INDIVIDUAL DIFFERENCES IN MOUSE BEHAVIORS CORRELATED WITH COMPULSIVE DRINKING BEHAVIOR, WORKING ACROSS THE PROJECTS TO IDENTIFY POPULATIONS OF PRECISE BEHAVIORS THAT ARE PREDICTIVE OF COMPULSIVE ETHANOL SEEKING. PROJECTS 2 AND 4 EXPLORE THERAPEUTIC TARGETS THROUGH ANALYSIS OF ENDOCANNABINOID AND DYNORPHIN SIGNALING. THE PROJECT INTERACTIONS WILL BE COORDINATED BY AN ADMINISTRATIVE CORE. A RESEARCH CORE WILL PROVIDE MICE THAT HAVE UNDERGONE ONE OF TWO VOLUNTARY ALCOHOL EXPOSURE MODELS, CHRONIC DRINKING-FORCED ABSTINENCE (CDFA) OR STRUCTURED TRACKING OF ALCOHOL REINFORCEMENT (STAR). IT WILL ALSO PROVIDE RESEARCH INFRASTRUCTURE AND COMPUTATIONAL SUPPORT. THROUGH A DISSEMINATION CORE, VAREC WILL PLAY AN IMPORTANT ROLE IN PUBLIC HEALTH BY ACTIVITIES AIMED AT DESTIGMATIZING AUD TREATMENT SEEKING AND INCREASING PREVENTION THROUGH NOVEL NEAR-PEER TARGETING OF ADOLESCENTS. THIS CORE WILL ALSO ALLOW VAREC TO SERVE AS A RESOURCE TO THE ALCOHOL RESEARCH COMMUNITY TO FACILITATE MAINSTREAM INCORPORATION OF CUTTING-EDGE TOOLS INTO THE FIELD.

DESIGN.R - ARTIFICIAL INTELLIGENCE (AI)-ASSISTED CYBER PHYSICAL SYSTEMS (CPS) DESIGN

META DESIGN FLOW DEFINITION AND IMPLEMENTATION

A MULTIMODAL 3D ATLAS OF COLORECTAL CANCER ACROSS AGES OF ONSET - PROJECT SUMMARY WE PROPOSE THE CONSTRUCTION OF A THREE-DIMENSIONAL (3D) MULTIMODAL MOLECULAR ATLAS OF COLORECTAL CANCER (CRC) ACROSS DIFFERENT AGES OF ONSET OF THE DISEASE. WE AIM TO ADDRESS THE EMERGING CLINICAL CHALLENGE OF RISING EARLY-ONSET CRC CASES BY EXPLORING MOLECULAR DIFFERENCES BETWEEN EARLY-ONSET AND LATER-ONSET CRCS. WE HYPOTHESIZE THAT ABERRANT INTERACTIONS BETWEEN THE CARCINOGENIC MICROBES, TUMOR METABOLIC NICHE, AND THE TUMOR MICROENVIRONMENT LEAD TO ACCELERATED TRANSITIONS OF PRECANCEROUS CELL STATES TO MALIGNANT STATES. OUR ATLAS WILL FOCUS ON SPATIALLY MAPPING TRANSITIONS FROM PRECANCEROUS TO CANCEROUS COMPONENTS WITHIN THE SAME TUMOR, UTILIZING A "PHYLOGEOGRAPHIC" MAPPING APPROACH TO CREATE INDIVIDUALIZED AND GLOBAL PROGRESSION TRAJECTORIES BETWEEN TUMOR SUBTYPES (EARLY ONSET CRCS, LATER-ONSET MICROSATELLITE STABLE CRCS, LATER-ONSET MICROSATELLITE UNSTABLE CRCS). WE EMPLOY CUTTING-EDGE TECHNOLOGIES, SUCH AS CUSTOMIZED SPATIAL TRANSCRIPTOMICS, CO-DETECTION BY INDEXING HIGHLY MULTIPLEXED IMMUNOFLUORESCENCE MICROSCOPY, UNTARGETED IMAGING MASS SPECTROMETRY, AND HISTOLOGICAL AND AUTOFLUORESCENCE IMAGING, TO COMPREHENSIVELY CHARACTERIZE CRC TISSUE AT VARIOUS MOLECULAR LEVELS AND SPATIAL SCALES. WE EMPLOY A 3D MULTIMODAL STRATEGY BY RECONSTRUCTING VOLUMES FROM INTERLEAVING SERIAL TISSUE SECTIONS EVALUATED BY DIFFERENT TECHNOLOGIES. PAIRED WHOLE EXOME SEQUENCING AND SINGLE-CELL RNA-SEQUENCING DATA WILL ANCHOR OUR SPATIAL ANALYSES TO OUR PREVIOUS HUMAN TUMOR ATLAS NETWORK (HTAN) DATA. WE LEVERAGE OUR PREVIOUS SUCCESS IN BUILDING COLORECTAL ATLASES WITHIN THE HTAN AND ENSURE THAT DATA ARE RELEASED FOR OPEN-ACCESS USE TO THE RESEARCH COMMUNITY. WE HAVE A STRONG TEAM WITH EXPERTISE IN GENOMIC PROFILING, MULTI-OMIC SPATIAL ANALYSIS, BIOSTATISTICS, AND ARTIFICIAL INTELLIGENCE. OUR PROPOSAL EMPHASIZES OUR TEAM'S EXTENSIVE TRACK RECORD IN CRC RESEARCH, WITH ACTIVE PROGRAMS IN CRC, GUT EPITHELIAL BIOLOGY, CRC MICROBIOME, EPIDEMIOLOGY, AND PATHOLOGY. OUR GOAL IS TO PROVIDE UNPRECEDENTED INSIGHTS INTO THE GENETIC, TRANSCRIPTOMIC, METABOLOMIC, MICROBIAL, AND ARCHITECTURAL FEATURES OF CRC IN A SPATIALLY RESOLVED MANNER TO BETTER UNDERSTAND CRCS ACROSS VARIOUS AGE GROUPS.

META II

NEW CONTRACT AWARD FOR THE COMPONENT USABILITY, REALIZABILITY, AND TRANSFORMATION ENGINE (CURATE) EFFORT.

D: COMPUTING THE BIOME

MEDICAL SCIENTIST TRAINING PROGRAM - THIS PROPOSAL REQUESTS SUPPORT FOR THE MEDICAL SCIENTIST TRAINING PROGRAM (MSTP) AT THE VANDERBILT UNIVERSITY SCHOOL OF MEDICINE. THE PROGRAM'S PRIMARY GOAL IS TO IDENTIFY, RECRUIT, TRAIN, AND MENTOR A DIVERSE WORKFORCE OF COMPASSIONATE AND DEDICATED FUTURE PHYSICIAN-SCIENTISTS. THESE VANDERBILT-TRAINED PHYSICIAN-SCIENTISTS WILL SERVE CRITICAL NEEDS IN ALL ASPECTS OF MEDICINE, SCIENCE, INDUSTRY, AND GOVERNMENT TO IMPROVE HUMAN HEALTH, REDUCE DISPARITIES, AND IMPROVE SOCIETY THROUGH LEADERSHIP IN BIOMEDICAL RESEARCH AND CLINICAL PRACTICE. OUR JOINT MD-PHD PROGRAM IS BASED ON RIGOROUS TRAINING IN CLINICAL MEDICINE AND SCIENTIFIC INQUIRY. CORE PROGRAM ELEMENTS EXPLICITLY DEVELOPED FOR DUAL-DEGREE STUDENTS INCLUDE A FOUNDATIONAL BIOMEDICAL COURSE, A LITERATURE-BASED SEMINAR SERIES, THE CLINICAL PRECEPTORSHIP PROGRAM, SEMINAR SERIES, LEADERSHIP WORKSHOPS, THE PHYSICIAN- SCIENTIST SPEAKER SERIES, EXTENSIVE NEAR-PEER MENTORING, A HOST OF STUDENT-LED INSTITUTIONAL AND COMMUNITY OUTREACH ACTIVITIES TO GIVE BACK TO THE COMMUNITY, AND AN ANNUAL RETREAT TO REINFORCE CONNECTIONS, HEAR ABOUT GREAT SCIENCE, AND LEARN TOGETHER. STUDENTS RECEIVE FORMAL INSTRUCTION IN QUANTITATIVE REASONING, RESPONSIBLE CONDUCT OF RESEARCH, AND RIGOR AND REPRODUCIBILITY THREADED AND REINFORCED THROUGHOUT THE CURRICULUM. AN INNOVATIVE ADVISING COLLEGE PROGRAM OFFERS OPPORTUNITIES FOR VERTICAL INTEGRATION OF FACULTY MEMBERS AND BOTH PHYSICIAN-SCIENTISTS IN RESIDENCY AND MSTP TRAINEES. CURRENT STUDENTS PLAY KEY ROLES IN STUDENT RECRUITMENT AND CURRICULUM DEVELOPMENT. OUR ALUMNI ARE EXCEPTIONALLY ACCOMPLISHED WHICH INCLUDE THE FOUNDING PRESIDENT OF THE GLADSTONE INSTITUTE, THREE DEANS, THREE DEPARTMENT CHAIRS, 26 FULL PROFESSORS, AND 18 INDUSTRY LEADERS. MORE RECENT GRADUATES STILL IN TRAINING ARE IN SUPERB RESIDENCIES AND FELLOWSHIPS. THE 109 CURRENT TRAINEES COME FROM 74 COLLEGES AND UNIVERSITIES DISTRIBUTED ACROSS NORTH AMERICA. THE GROWTH OF OUR NATIONWIDE APPLICANT POOL RESULTS FROM CONCERTED RECRUITING EFFORTS, INCLUDING THOSE FOCUSED ON RECRUITING STUDENTS FROM UNDERREPRESENTED GROUPS IN MEDICINE. IN THE CURRENT YEAR, 595 APPLICATIONS HAVE BEEN RECEIVED, FROM WHICH 15 STUDENTS WILL BE SELECTED TO ENTER THE INCOMING CLASS. THE EDUCATIONAL ENVIRONMENT FOR PHYSICIAN-SCIENTISTS AT VANDERBILT UNIVERSITY RANKED #12 IN NIH FUNDING, IS OUTSTANDING AND BUILT ON ESTABLISHED STRENGTHS IN BIOMEDICAL INFORMATICS, CANCER BIOLOGY, CELL BIOLOGY, CLINICAL PHARMACOLOGY, DIABETES, NEUROSCIENCES, TOXICOLOGY, DRUG DISCOVERY, GENETICS, CHEMICAL AND PHYSICAL BIOLOGY, IMAGING SCIENCES, MICROBIAL PATHOGENESIS, PHARMACOGENOMICS, AND VACCINE SCIENCE. NEWER AREAS OF RESEARCH EMPHASIZE IMMUNOBIOLOGY, INFLAMMATION AND CANCER, PRECISION MEDICINE, QUANTITATIVE SYSTEMS BIOLOGY, AND STRUCTURAL BIOLOGY. BASED ON THE COMMITMENT OF OUR LEADERSHIP TEAM, THE STRENGTH OF OUR APPLICANT POOL, ENHANCED OPPORTUNITIES FOR PHYSICIAN-SCIENTIST TRAINING, A LONGSTANDING INSTITUTIONAL COMMITMENT TO THE EDUCATION OF MSTP LEADERS IN BIOMEDICAL RESEARCH, AND THE SUCCESS OF OUR GRADUATES IN ACADEMIC MEDICINE, THIS PROPOSAL REQUESTS AN INCREASE IN POSITIONS TO 27 FOR THE FIVE-YEAR PROJECT PERIOD.

ADVANCED NURSING EDUCATION WORKFORCE

EMERGENT LIGHT-MATTER INTERACTIONS THROUGH TWISTED ATOMIC AND PHOTONIC CRYSTALS

EARLY ACADEMIC ACHIEVEMENT AND INTERVENTION RESPONSE: ROLE OF EXECUTIVE FUNCTION

IGF::OT::IGF:: MONITORING AND COORDINATING PERSONAL PROTECTIVE EQUIPMENT (PPE)

SINGLE CELL METHODS FOR BIOEFFECTOR DISCOVERY AND ANALYSIS

DECODING THE FUNCTIONS OF MYOSIN II ISOFORMS WITH SUPER-RESOLUTION MICROSCOPY

DYNAMIC ARCHITECTURE OF MICROTUBULE NETWORKS

THE TENNESSEE SPACE GRANT CONSORTIUM THOUGH PROGRAMMATICALLY DE-CENTRALIZED SHARES COMMON GOALS OBJECTIVES FOR THE UPCOMING AWARD PERIOD.

TRACK 4 (PHASE II): THE AUTISM SELF-ADVOCACY CENTER FOR EQUITY AND NEURODIVERSITY IN ENGINEERING (THE A-SCENE) -NEURODIVERSITY IS AN EMERGING PARADIGM THROUGH WHICH NEUROLOGICAL DIFFERENCES, TRADITIONALLY VIEWED ONLY IN TERMS OF DISABILITY -- AUTISM SPECTRUM DISORDERS, ATTENTION DEFICIT HYPERACTIVITY DISORDER, DYSLEXIA -- ARE INSTEAD VIEWED AS HUMAN VARIATIONS HAVING ASSOCIATED IMPAIRMENTS BUT ALSO UNIQUE STRENGTHS HIGHLY RELEVANT TO STEM. YET THIS GROUP, NOW REPRESENTING AT LEAST 20% OF THE US POPULATION, DOES NOT SUFFICIENTLY PARTICIPATE IN THE STEM WORKFORCE: RECENT WORK SUGGESTS THAT ONLY 11% OF STEM UNDERGRADUATES ARE NEURODIVERSE, AND A 2021 NSF REPORT SUGGESTS THAT ONLY 4.4% OF ALL STEM PHD RECIPIENTS ARE NEURODIVERSE. GROWING RESEARCH EVIDENCE SUGGESTS ENHANCED ABILITIES AND SKILLS IN NEURODIVERSE LEARNERS HIGHLY RELEVANT TO THE ENGINEERING WORKFORCE. EXAMPLES INCLUDE ENHANCED DIVERGENT THINKING IN ADHD, SUCCESS IN COMPETITIVE COLLEGES FOR AUTISTIC STUDENTS, AND ENHANCED COGNITIVE AND SOCIO-EMOTIONAL RESILIENCE, VISUO-SPATIAL ABILITY, AND EMOTIONAL REACTIVITY WITH CORRESPONDING NEURAL DIFFERENCES IN DYSLEXIA. THIS PROJECT WILL ADDRESS THE OPPORTUNITY TO MORE FULLY ENABLE THIS UNDERUTILIZED WORKFORCE BY STANDING UP A NEW CENTER CALLED THE AUTISM SELF-ADVOCACY CENTER FOR EQUITY AND NEURODIVERSITY IN ENGINEERING (A-SCENE). THE PROJECT?S VISION IS TO MODEL A FULLY INTERCONNECTED SYSTEM OF PROGRAMS, ACTIVITIES, AND SUPPORTS TO ENSURE THAT NEURODIVERSE STUDENTS CAN ACCESS AND SUCCEED IN ENGINEERING CAREERS, FROM THE UNDERGRADUATE EXPERIENCE, TO GRADUATE TRAINING AND PROFESSIONAL DEVELOPMENT, TO MEANINGFUL ENGAGEMENT IN THE STEM WORKFORCE. THE CENTER WILL PILOT AND INNOVATE ITS SIGNATURE PROGRAMS AMONG THE INITIAL PARTNER UNIVERSITIES (VANDERBILT UNIVERSITY, FISK UNIVERSITY, UNIVERSITY OF CONNECTICUT, AND NORTHEASTERN UNIVERSITY), DEVELOP AN ENGINEERING NEURODIVERSITY PLAYBOOK FOR ADOPTION OF THE A-SCENE MODEL BY ANY ENGINEERING SCHOOL, AND THEN SYSTEMATICALLY EXPAND THROUGH A LONG-TERM SUSTAINABLE AFFILIATE UNIVERSITIES PROGRAM, WITH THE GOAL TO EVENTUALLY REACH ALL ENGINEERING SCHOOLS IN THE NATION. THE A-SCENE PHASE II EFFORT BUILDS ON THE UNIQUE STRENGTHS OF THE CORE UNIVERSITY PARTNERS, BRINGING TOGETHER EXTANT EFFORTS INCLUDING VANDERBILT?S FRIST CENTER FOR AUTISM & INNOVATION, THE FISK-VANDERBILT 3+2 PROGRAM IN ENGINEERING, FISK?S INSTITUTE FOR NEURODIVERSITY & INTERSECTIONALITY, UCONN?S NEURODIVERSITY TEACHING INSTITUTE, NORTHEASTERN?S SIGNATURE CO-OP PROGRAM, AND THE NATIONAL COLLEGE AUTISM NETWORK, ITSELF REPRESENTING MORE THAN 125 COLLEGE AND UNIVERSITY MEMBERS. ARIZONA STATE AND UNIVERSITY OF ILLINOIS JOIN AS A-SCENE?S INAUGURAL AFFILIATE PARTNERS, EXTENDING OUR GEOGRAPHICAL REACH AND DIVERSITY OF STUDENTS. A-SCENE WILL REACH A LARGE COMMUNITY OF NEURODIVERSE INDIVIDUALS AT THE PARTNER INSTITUTIONS AS WELL AS MUCH MORE BROADLY THROUGH DISSEMINATION OF THE MODEL AND PLAYBOOK NATIONALLY. DURING THIS PHASE II EFFORT, A-SCENE WILL ESTABLISH MECHANISMS FOR LONG-TERM CONTINUITY AND GROWTH OF A-SCENE NATIONALLY BY: (A) CURATING THE ENGINEERING NEURODIVERSITY PLAYBOOK, INCLUDING CURRICULA, GUIDES, RUBRICS, AND OTHER MATERIALS AS A LIVING ONLINE RESOURCE; (B) EXPANDING THE AFFILIATES PROGRAM THROUGH MEMBERSHIP FEES TO SUPPORT ONGOING GROWTH OF THE A-SCENE NETWORK; (C) CREATION OF A NATIONAL STUDENT ORGANIZATION -- THE SOCIETY OF NEURODIVERSE ENGINEERS -- WITH LOCAL CHAPTERS AND NATIONAL ACTIVITIES SUPPORTED THROUGH DUES; (D) EXPLORING A FEE STRUCTURE FOR ACCESS TO TRAININGS FOR STUDENT-SUPPORT PROFESSIONALS AND ACCESS TO EMPLOYER EDUCATION SERVICES; AND (E) EXPLORING A LICENSING FEE STRUCTURE FOR USE OF A-SCENE?S INTERNSHIP- AND JOB-MATCHING TOOL. WE WILL CONTINUALLY ENGAGE ADDITIONAL AFFILIATE PARTNER INSTITUTIONS, WHICH WILL FURTHER AMPLIFY THE DIRECT IMPACT OF THIS EFFORT. AT THE LARGEST SCALE, ENGINEERING UNDERGRADUATE AND GRADUATE STUDENTS NATIONWIDE NOW NUMBER MORE THAN 700,000, OF WHOM ~77,000 ARE EXPECTED TO BE NEURODIVERSE. TO BE SURE, THESE ESTIMATES ARE PROJECTIONS BEYOND THIS PHASE II EFFORT, BUT THEY SUGGEST THAT THE POTENTIAL FOR BROAD IMPACT ON THE NEURODIVERSE POPULATION IN ENGINEERING IS LARGE. FINALLY, DISSEMINATION OF THE A-SCENE ENGINEERING NEURODIVERSITY PLAYBOOK THROUGH INCLUDES, ABET, AND OTHER NATIONAL NETWORKS WILL BROADEN THE IMPACT FURTHER STILL. 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 PLANNED FOR THIS AWARD.

RADIATION EFFECTS CENTER OF EXCELLENCE

EQUIPMENT: MRI: TRACK 2 - DEVELOPMENT OF A MALDI TRAPPED ION MOBILITY FT-ICR MASS SPECTROMETRY PLATFORM FOR HIGH-PERFORMANCE MOLECULAR IMAGING AND TRAINING -THIS INSTRUMENT DEVELOPMENT PROJECT WILL CONSTRUCT A NEXT-GENERATION MOLECULAR IMAGING INSTRUMENT TO VISUALIZE BIOLOGICAL TISSUES AND ENGINEERED MATERIALS THAT MIMIC BIOLOGICAL SYSTEMS. BY INTEGRATING ADVANCED LASER OPTICS, CUSTOM ION SOURCE DESIGN, GAS-PHASE SEPARATION STRATEGIES, AND HIGH-RESOLUTION MASS SPECTROMETRIC ANALYSIS, THIS INSTRUMENT WILL PROVIDE REVOLUTIONARY CAPABILITIES FOR VISUALIZING BIOLOGICAL MOLECULES. THE NEW INSTRUMENT WILL HELP EXPAND THE UNDERSTANDING OF CELLULAR SYSTEMS. THE PROJECT WILL BE CONDUCTED IN CLOSE PARTNERSHIP WITH LEADING INVESTIGATORS WHO ARE WORKING TO SOLVE EMERGING CHALLENGES IN BIOTECHNOLOGY AND HUMAN HEALTH. THESE COLLABORATIONS ARE INTENTIONALLY SELECTED TO DRIVE ITERATIVE CO-DEVELOPMENT AND MAXIMIZE REAL-WORLD IMPACT. THE RESULTING PLATFORM WILL BROADEN THE AVAILABILITY OF HIGH-PERFORMANCE IMAGING CAPABILITIES TO RESEARCHERS IN ACADEMIA, FEDERAL LABORATORIES, AND PRIVATE INDUSTRY. THE INSTRUMENT WILL BE HOUSED WITHIN THE VANDERBILT UNIVERSITY MASS SPECTROMETRY RESEARCH CENTER, A NATIONALLY RECOGNIZED HUB FOR MOLECULAR IMAGING AND MASS SPECTROMETRY, AND IT WILL SERVE TO TRAIN NEW GENERATIONS OR RESEARCHERS. THIS PROJECT WILL STRENGTHEN NATIONAL INFRASTRUCTURE, EXPAND ACCESS TO ADVANCED TECHNOLOGIES, AND PROVIDE ADVANCED CAPABILITIES FOR MOLECULAR DISCOVERY AND BIOLOGICAL RESEARCH. THE INSTRUMENT TO BE DEVELOPED IS A STATE-OF-THE-ART MATRIX-ASSISTED LASER DESORPTION/IONIZATION IMAGING MASS SPECTROMETRY PLATFORM THAT INTEGRATES TRAPPED ION MOBILITY SPECTROMETRY WITH FOURIER TRANSFORM ION CYCLOTRON RESONANCE FOR HIGH-SPECIFICITY MOLECULAR IMAGING AT CELLULAR SPATIAL RESOLUTION. LEVERAGING THE HIGH-FIELD 15 TESLA MAGNET FROM A DECOMMISSIONED INSTRUMENT, THE PROJECT WILL COMBINE ION MOBILITY GAS-PHASE ION SEPARATION WITH A CUSTOM OMNITRAP COLLISION CELL FOR MULTI-MODE FRAGMENTATION AND THE ULTRA-HIGH MASS RESOLVING POWER OF FOURIER TRANSFORM ION CYCLOTRON RESONANCE MASS SPECTROMETRY. THIS UNIQUE PLATFORM WILL ENABLE DEEP ANALYSIS OF ISOBARIC AND ISOMERIC CHEMICAL SPECIES, HIGH SPATIAL RESOLUTION MOLECULAR IMAGING (<5 MICRON PIXEL SIZES), ULTRA-HIGH MASS RESOLVING POWER (>1,000,000), AND COMPREHENSIVE STRUCTURAL CHARACTERIZATION OF A WIDE RANGE OF BIOMOLECULES. HOUSED AT THE VANDERBILT MASS SPECTROMETRY RESEARCH CENTER, THE PLATFORM WILL SERVE AS A CORNERSTONE FOR INTERDISCIPLINARY RESEARCH ACROSS BIOLOGY, ENGINEERING, AND MEDICINE, AND WILL SUPPORT EXTENSIVE TRAINING ACTIVITIES THROUGH ESTABLISHED WORKSHOPS AND COLLABORATIVE ACTIVITIES. THE SYSTEM REPRESENTS A MAJOR ADVANCE IN MOLECULAR IMAGING CAPABILITIES, PROVIDING THE SCIENTIFIC COMMUNITY WITH A POWERFUL TOOL FOR ANSWERING COMPLEX BIOLOGICAL QUESTIONS, ACCELERATING DISCOVERY, AND ADVANCING THE FRONTIERS OF SPATIAL OMICS. 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.

DRUG REPOSITIONING FOR ALZHEIMER'S DISEASE VIA GENETICS, ELECTRONIC HEALTH RECORDS, AND HUMAN IPSC MODELS - ALZHEIMER'S DISEASE (AD) IS A PROGRESSIVE NEURODEGENERATIVE DISEASE AND THE LEADING CAUSE OF DEMENTIA IN THE UNITED STATES. UNFORTUNATELY, THERE IS NO CURE FOR AD. DRUG DISCOVERY FOR AD HAS SUFFERED SIGNIFICANT FAILURES, MANY AT LATE STAGE CLINICAL TRIALS, PARTLY DUE TO OUR POOR UNDERSTANDING OF AD PATHOLOGY AND THE LACK OF DISEASE-RELEVANT AND HUMAN-RELEVANT DISCOVERY AND DEVELOPMENT MODELS. THIS CALLS FOR TEAM EFFORTS WITH DIVERSE AND COMPLEMENTARY EXPERTISE TO TACKLE THE CHALLENGES TOGETHER, BY DEVELOPING INNOVATIVE APPROACHES FROM MULTIPLE ANGLES TO ACHIEVE THE GOAL OF IDENTIFYING AD DRUGS. IN THIS APPLICATION, WE PROPOSE THREE COMPLEMENTARY SPECIFIC AIMS THAT TOGETHER AIM TO IDENTIFY FDA APPROVED DRUGS WITH REPURPOSE POTENTIAL FOR AD, FROM DISTINCT BUT COMPLEMENTARY ANGLES THAT ACT SYNERGISTICALLY TO BOOST THE LIKELIHOOD OF SUCCESS. AD IS A HIGHLY HERITABLE DISEASE, WITH AN ESTIMATED HERITABILITY OF 70%, HIGHLIGHTING THE CRITICAL ROLE OF GENETICS IN UNDERSTANDING THE DISEASE ETIOLOGY. RECENT GENETIC STUDIES HAVE IDENTIFIED OVER 30 LOCI, ENABLING US TO DISSECT THE GENETIC ARCHITECTURE OF AD, INCLUDING THE BIOLOGICAL PROCESSES AND CELL TYPES INVOLVED IN DISEASE ETIOLOGY. IN PARTICULAR, WE AIM TO DISSECT THE HIGHLY POLYGENIC AD ETIOLOGY INTO DISTINCT PATHOPHYSIOLOGICAL COMPONENTS TO GUIDE DRUG REPURPOSING, WHICH IS ONLY FEASIBLE IN RECENT YEARS THANKS TO LARGE SCALE GWAS AND MASSIVE GENOMICS DATA AVAILABLE PUBLICLY (AIM 1). IN PARALLEL, WE WILL MINE MILLIONS OF ELECTRONIC HEALTH RECORDS (EHRS) TO IDENTIFY DRUGS THAT REDUCE AD RISK AND COGNITIVE DECLINE, BY DEVELOPING PHENOTYPING ALGORITHMS FROM EHR FOR AD RELATED PHENOTYPES (AIM 2). IN ADDITION, WE WILL DEVELOP A HIGH­ THROUGHPUT SCREENING (HTS) GENE EXPRESSION PROFILING ASSAY AND USE HUMAN INDUCED PLURIPOTENT STEM CELL (IPSC) MODELS TO IDENTIFY CANDIDATE COMPOUNDS, AND WILL FURTHER TEST THE EFFICACY OF THE CANDIDATES IN BOTH PATIENT-DERIVED IPSC LINES AND AD MOUSE MODELS (AIM 3). THE THREE AIMS ARE COMPLEMENTARY AND SYNERGISTIC, IN THE SENSE THAT THEY INDEPENDENTLY TACKLE THE SAME PROBLEM FROM DRASTICALLY DISTINCT ANGLES, WHILE FINDINGS FROM ONE CAN BE SERVED AS VALIDATION FOR OTHERS. ALTOGETHER, LEVERAGING DISTINCT AND COMPLEMENTARY EXPERTISE, WE EXPECT TO YIELD BONA FIDE REPURPOSABLE DRUGS FOR AD WITH ORTHOGONAL SUPPORT.

SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

PARENT-CHILD PROXIMITY AND EMERGING PSYCHOPATHOLOGY - PROJECT SUMMARY/ABSTRACT THE CAREGIVING ENVIRONMENT CHILDREN EXPERIENCE IS THE MOST IMPORTANT MODIFIABLE FEATURE FOR SHAPING BRAIN DEVELOPMENT AND INFLUENCING SUBSEQUENT MENTAL HEALTH. BUILDING FROM KNOWLEDGE OF INFANT MENTAL HEALTH AND DEVELOPMENTAL NEUROSCIENCE, THIS NIMH BRAINS AWARD APPLICATION IS DESIGNED TO ADVANCE OUR UNDERSTANDING OF HOW CHILDREN’S EXPERIENCES WITH THEIR CAREGIVERS DURING INFANCY, A DEVELOPMENTAL PERIOD CHARACTERIZED BY HEIGHTENED BRAIN PLASTICITY, INFLUENCES BRAIN AND BEHAVIORAL DEVELOPMENT. SPECIFICALLY, WE WILL USE INNOVATIVE METHODS TO CHARACTERIZE MULTIPLE ASPECTS OF THE EARLY CAREGIVING ENVIRONMENT IN RELATION TO CHANGES IN BRAIN STRUCTURAL AND FUNCTIONAL CONNECTIVITY THAT ARE BELIEVED TO CONTRIBUTE TO THE ONSET OF MENTAL DISORDERS. THE APPLICATION OF NEW TOOLS, COUPLED WITH TRADITIONAL METRICS, WILL IMPROVE OUR MEASUREMENT OF CHILDREN’S EXPERIENCES USING A CHILD-CENTERED APPROACH (I.E., CAPTURING CHILDREN’S CONTACT WITH MULTIPLE CAREGIVERS). TO DO THIS, WE WILL RECRUIT 150 WOMEN IN PREGNANCY AND, FOLLOWING BIRTH, CONDUCT ASSESSMENTS IN CHILDREN’S DAILY ECOLOGICAL CONTEXT AT AGES 1, 6, 12, AND 18 MONTHS. THIS PROJECT INTRODUCES A WEARABLE DEVICE TECHNOLOGY THAT CAN DYNAMICALLY, UNOBTRUSIVELY, AND CONTINUOUSLY MEASURE PATTERNS OF PHYSICAL PROXIMITY BETWEEN CHILDREN AND CAREGIVERS, REGARDLESS OF PHYSICAL LOCATION. IN ADDITION TO CHILDREN’S PROXIMITY TO CAREGIVERS, WE WILL OBTAIN ECOLOGICAL ASSESSMENTS OF LANGUAGE EXPOSURE AND OBSERVATION-BASED CAREGIVER SENSITIVITY AND EXAMINE THE CONVERGENCE AND DIVERGENCE AMONG THESE DIFFERENT WAYS OF CAPTURING CHILDREN’S EXPERIENCES (SPECIFIC AIM 1). WHILE PRIOR RESEARCH SUGGESTS THAT GREATER ENVIRONMENTAL ENRICHMENT LEADS TO LOWER SYMPTOMS OF PSYCHOPATHOLOGY, THE LACK OF GRANULARITY IN MEASUREMENT (I.E., NOT CAPTURING THE FULL CONTINUUM OF RELATIVE PSYCHOSOCIAL NEGLECT–ENRICHMENT) HAS PRECLUDED THE ABILITY TO CHARACTERIZE THE SHAPE OF THESE ASSOCIATIONS (E.G., LINEAR, NONLINEAR). WE WILL STUDY CHILDREN SELECTED TO RANGE IN EXPERIENCES ALONG THE NEGLECT–ENRICHMENT CONTINUUM AND USE REPEATED NEUROIMAGING OF INFANT BRAIN STRUCTURAL AND FUNCTIONAL CONNECTIVITY AND REPEATED BEHAVIORAL ASSESSMENTS TO EXPLORE THE POSSIBLE PROFILE OF THE ASSOCIATIONS BETWEEN ASPECTS OF THE CAREGIVING ENVIRONMENT AND CHANGES IN BRAIN AND BEHAVIOR (SPECIFIC AIM 2). LAST, WE WILL EXAMINE HOW CHANGES IN EMOTION REGULATION AND EMOTION REASONING CIRCUITRY ARE ASSOCIATED WITH SIGNS OF EMERGING PSYCHOPATHOLOGY AT AGE 18 MONTHS IN ORDER TO TEST WHETHER, WHEN, AND HOW VARIATIONS IN EARLY EXPERIENCE INFLUENCE RISK FOR PSYCHOPATHOLOGY THROUGH CHANGES IN EMOTION-RELATED CIRCUITRY (SPECIFIC AIM 3). HERE, NEUROIMAGING IS PARTICULARLY ADVANTAGEOUS AS IT ALLOWS US TO EXAMINE THE MATURATION OF EMOTION-RELATED NETWORKS FROM BIRTH AND, IMPORTANTLY, PRIOR TO THE ONSET OF DETECTABLE MENTAL HEALTH DIFFICULTIES. ACHIEVEMENT OF THE AIMS OF THIS PROPOSAL IS EXPECTED TO MEET NIMH’S OBJECTIVES TO DETERMINE THE BIOLOGICAL AND PSYCHOLOGICAL MECHANISMS BY WHICH EXPERIENCE AFFECTS NEURAL AND BEHAVIORAL DEVELOPMENT, WITH DIRECT APPLICATIONS FOR PREVENTION AND EARLY INTERVENTION.

FUNCTIONS OF SRAP DOMAIN PROTEINS IN DNA METABOLISM

VEHICLEFORGE.MIL - THE CONTRACTOR SHALL DEVELOP, OPERATE AND SUPPORT AN OPEN SOURCE COLLABORATION AND HOSTING WEBSITE FOR MODEL-BASED DEVELOPMENT OF GROUND VEHICLES AND SIMILAR CYPER-ELECTRO-MECHANICAL SYSTEMS.

ADVANCED NURSE EDUCATION-SEXUAL NURSE ASSAULT EXAMINER PROGRAM

POINT-OF-CARE RT-PCR SYSTEM TO INFORM COVID-19 AND RESPIRATORY ILLNESS DECISIONS

PERIVASCULAR FIBROBLASTS, VASCULAR FIBROSIS, AND THEIR CONTRIBUTIONS TO CEREBRAL AMYLOID ANGIOPATHY - PROJECT SUMMARY CEREBRAL AMYLOID ANGIOPATHY (CAA) IS A DISEASE THAT OCCURS WHEN AMYLOID BETA (ASS) FORMS DEPOSITS ON BRAIN BLOOD VESSELS. CAA FREQUENTLY CO-OCCURS WITH ALZHEIMER’S DISEASE (AD) AND IS A SIGNIFICANT RISK FACTOR FOR INTRACRANIAL HEMORRHAGE AND DEMENTIA. THERE ARE NO APPROVED TREATMENTS FOR CAA, AND THE MOLECULAR ETIOLOGY OF THE DISEASE REMAINS UNCLEAR, WHICH HAS PREVENTED THE DEVELOPMENT OF EFFECTIVE THERAPEUTIC INTERVENTIONS. HERE, WE PROPOSE TO STUDY CEREBRAL PERIVASCULAR FIBROBLASTS AND VASCULAR FIBROSIS SIGNALING PATHWAYS AS POTENTIAL CONTRIBUTORS TO CAA PATHOLOGY. MORE THAN 20 YEARS AGO, PIONEERING WORK SHOWED THAT ASTROCYTE-SPECIFIC UPREGULATION OF TRANSFORMING GROWTH FACTOR BETA 1 (TGFSS1), A MASTER REGULATOR OF TISSUE FIBROSIS, COULD SPECIFICALLY INDUCE ASS PATHOLOGY IN THE CEREBROVASCULATURE THAT WAS REMINISCENT OF CAA. HOWEVER, THE MECHANISTIC ACTIONS OF TGFSS1 THAT COULD DRIVE SUCH A RESPONSE WERE NEVER ELUCIDATED. IN STUDYING POSTMORTEM HUMAN BRAIN TISSUE FROM CAA PATIENTS, WE HAVE FOUND THAT CEREBRAL PERIVASCULAR FIBROBLASTS ACQUIRE MYOFIBROBLAST MARKERS AROUND VESSELS WITH ASS DEPOSITION AND FIBROTIC SIGNATURES—THIS PHENOTYPE IS OBSERVED SPECIFICALLY IN CAA BUT NOT AD OR AGE-MATCHED CONTROLS. FURTHER, THIS PHENOTYPE IS REPLICATED IN 5XFAD MICE AFTER INTRACEREBROVENTRICULAR INJECTIONS OF HUMAN VASCULAR-DERIVED HUMAN ASS SEEDS, WHICH YIELDS CAA-LIKE PATHOLOGY. HENCE, WE HYPOTHESIZE THAT ACTIVATION OF PERIVASCULAR FIBROBLASTS AND FIBROTIC SIGNALING PATHWAYS IN THE PERIVASCULAR NICHE LEADS TO ASS DEPOSITION, VASCULAR FIBROSIS, AND ACQUISITION OF THE CAA PHENOTYPE. IN AIM 1, WE WILL EXPLORE THIS HYPOTHESIS WITHIN TWO COMPLEMENTARY MOUSE MODELS USING THREE-DIMENSIONAL TISSUE IMAGING TECHNIQUES, SINGLE-CELL RNA SEQUENCING, AND BLOOD FLOW MEASUREMENTS. IN AIM 2, WE WILL LEVERAGE A NOVEL BIOENGINEERED MODEL OF HUMAN CEREBRAL ARTERIOLES TO UNDERSTAND HOW TGFSS1 SHAPES THE FIBROTIC MICROENVIRONMENT THROUGH MULTICELLULAR CROSSTALK. IN AIM 3, AGAIN IN MOUSE MODELS, WE WILL TARGET CEREBRAL PERIVASCULAR FIBROBLASTS AND FIBROTIC SIGNALING PATHWAYS USING GENE SILENCING TECHNIQUES AND SMALL MOLECULE TREATMENTS AND DETERMINE IF CAA PATHOLOGY IS LESSENED. COLLECTIVELY, THESE STUDIES WILL UNVEIL AND CHARACTERIZE HOW PERIVASCULAR FIBROBLASTS AND VASCULAR FIBROSIS CONTRIBUTE TO CAA PATHOLOGY. MOREOVER, THESE INVESTIGATIONS WILL IDENTIFY POTENTIAL PRECLINICAL DRUG DEVELOPMENT STRATEGIES FOCUSED ON TARGETING FIBROBLAST ACTIVATION AND SIGNALING PATHWAYS THAT CONTRIBUTE TO A PRO- FIBROTIC MICROENVIRONMENT IN CAA.

EFFECTIVENESS OF LEVELED LITERACY INTERVENTION INTERMEDIATE FOR THIRD AND FOURTH GRADE STUDENTS WITH READING DIFFICULTIES OR DISABILITIES

STRUCTURAL BIOLOGY OF THE DNA REPLICATION STRESS RESPONSE

CYBER AGENTS FOR SECURITY TESTING AND LEARNING ENVIRONMENTS (CASTLE) PROGRAM.

TARGETING NEGATIVE AFFECT THROUGH MINDFULNESS TRAINING IN YOUTH AT RISK FOR INTERNALIZING PROBLEMS - PROJECT SUMMARY RATES OF ANXIETY AND DEPRESSION IN YOUTH ARE SUBSTANTIAL, CAUSING A MAJOR UNMET NEED FOR EFFECTIVE INTERVENTIONS. ALTHOUGH SOME PROGRESS HAS BEEN MADE IN PREVENTING THESE INTERNALIZING PROBLEMS IN ADOLESCENTS, FURTHER RESEARCH IS NEEDED THAT SPECIFICALLY TARGETS THEORETICALLY AND EMPIRICALLY SUPPORTED RISK PROCESSES. AN IMPORTANT AND SALIENT RISK FACTOR FOUND TO INCREASE THE LIKELIHOOD OF ANXIETY AND DEPRESSION IS NEGATIVE AFFECTIVITY – A PARTIALLY HERITABLE TRAIT PROPENSITY TO EXPERIENCE AND EXPRESS MORE FREQUENT, INTENSE, AND ENDURING AVERSIVE EMOTIONAL STATES. THE PROPOSED RANDOMIZED CONTROLLED PREVENTION TRIAL BUILDS ON OUR FINDING FROM OUR LONGITUDINAL STUDY THAT ELEVATED LEVELS OF NEGATIVE AFFECTIVITY DURING ADOLESCENCE PROSPECTIVELY PREDICTED INTERNALIZING DISORDERS IN EARLY ADULTHOOD (ZINBARG ET AL., 2016); MOREOVER, THIS RELATION WAS MEDIATED BY CHANGES IN MOMENTARY NEGATIVE AFFECT (MNA) MEASURED WITH ECOLOGICAL MOMENTARY ASSESSMENT (EMA) (ADAM ET AL., 2018). THE FIRST PHASE (R61) OF THE PROPOSED SELECTIVE PREVENTION TRIAL WILL TEST WHETHER AN APP-BASED, COACH-SUPPORTED MINDFULNESS INTERVENTION AS COMPARED TO AN ASSESSMENT-ONLY CONTROL REDUCES MOMENTARY NEGATIVE AFFECT, MEASURED WITH ECOLOGICAL MOMENTARY ASSESSMENT (EMA), IN 120 ADOLESCENTS (AGE 12-16) AT- RISK BASED ON THEIR HAVING HIGH LEVELS OF TRAIT NEGATIVE AFFECTIVITY. EMA WILL BE USED TO MEASURE AVERAGE DAILY MOOD, (THE “TARGET”) COLLECTED SIX TIMES A DAY ACROSS THREE DAYS AT PRE-, MID-, AND POST- INTERVENTION. “TARGET” ENGAGEMENT WILL BE DEFINED AS A MEDIUM EFFECT SIZE (>.40) IN THE COMPARISON OF YOUTH RANDOMIZED TO MBI VERSUS CONTROL ON THE TARGET – MOMENTARY NEGATIVE AFFECT – AT POST-TEST, ADJUSTING FOR PRE-TEST LEVELS. WE ALSO WILL ASSESS THE DOSE-RESPONSE RELATION BY TESTING THE ASSOCIATION BETWEEN NUMBER OF SESSIONS AND EXERCISES COMPLETED WITH CHANGES IN MOMENTARY NEGATIVE AFFECT AND WEEKLY MOOD RATINGS. IN THE SECOND PHASE (R33), WE WILL CONDUCT A REPLICATION TRIAL WITH A NEW SAMPLE OF 360 AT-RISK (I.E., HIGH TRAIT NEGATIVE AFFECTIVITY) YOUTHS (AGES 12-16) RANDOMIZED TO ONE OF THREE CONDITIONS – MBI, A NONSPECIFIC CONTROL, OR AN ASSESSMENT-ONLY CONTROL. YOUTH WILL BE EVALUATED WITH REGARD TO THE TARGET (I.E., MNA), INTERNALIZING SYMPTOMS AND DISORDERS, AND FUNCTIONING (E.G., SOCIAL, ACADEMIC) AT BASELINE AND POST-INTERVENTION (R61 AND R33), AND AT A 6-MONTH FOLLOW-UP (R33). FINALLY, IN THE R33 WE WILL TEST IF SIGNIFICANT REDUCTIONS IN MOMENTARY NEGATIVE AFFECT ARE ASSOCIATED WITH IMPROVEMENTS (OR LESS WORSENING) IN INTERNALIZING SYMPTOMS AND FEWER ONSETS OF INTERNALIZING DISORDERS.