XAVIER UNIVERSITY OF LOUISIANA

ASSESSING VACCINE HESITANCY AND A PHARMACIST LED INTERVENTION MODEL TO INCREASE COVID-19 VACCINE UPTAKE AMONG AFRICAN AMERICANS

HISTORICALLY BLACK COLLEGES AND UNIVERSITIES PROGRAM

CENTERS OF EXCELLENCE (HBCU)

UNKNOWN TITLE

GRANT PROGRAM

GRANT PROGRAM

STRENGTHENING XULA'S GRADUATE PROGRAMS THROUGH HBGI FUNDING

GRANT PROGRAM

HISTORICALLY BLACK COLLEGES AND UNIVERSITIES PROGRAM (FUTURE ACT)

COLLABORATIVE RESEARCH: XULA-UCHICAGO PARTNERSHIP FOR RESEARCH AND EDUCATION IN INNOVATIVE COMPOSITE MATERIALS -THE OVERALL AIM OF THE PARTNERSHIP FOR RESEARCH AND EDUCATION IN MATERIALS (PREM) BETWEEN XAVIER UNIVERSITY OF LOUISIANA (XULA) AND THE UNIVERSITY OF CHICAGO (UCHICAGO) MATERIALS RESEARCH SCIENCE AND ENGINEERING CENTER (MRSEC) IS TO BROADEN PARTICIPATION IN MATERIALS SCIENCE AND ENGINEERING CAREERS BY ENGAGING UNDERGRADUATE STUDENTS IN CUTTING-EDGE RESEARCH. THIS PROJECT IS SIGNIFICANT TO THE NATIONAL INTEREST BECAUSE OF ITS FOCUS ON PREPARING HOME-GROWN TALENT FOR SPECIALIZED CAREERS IN MATERIALS SCIENCE AND ENGINEERING. IN ADDITION, THE TWO RESEARCH THRUSTS PROPOSED IN THIS PROJECT ARE DIRECTLY ALIGNED WITH ACHIEVING NATIONAL ENERGY INDEPENDENCE. SPECIFICALLY, THIS PROJECT FOCUSES ON DEVELOPING NEW COMPOSITE MATERIALS FOR HIGH ENERGY DENSITY BATTERY SYSTEMS. BY FOCUSING ON ENHANCING BOTH THE IONIC CONDUCTIVITY AND ELECTROCHEMICAL STABILITY OF SOLID ELECTROLYTES, THIS PROJECT WILL LEAD TO NEW MATERIALS WITH THE POTENTIAL TO IMPROVE THE LONG-TERM CYCLABILITY AND ENERGY DENSITY OF RECHARGEABLE BATTERY SYSTEMS FOR PORTABLE ENERGY STORAGE APPLICATIONS. BEYOND RESEARCH, THIS PROJECT ALSO SEEKS TO ENGAGE A YOUNGER GENERATION IN MATERIALS SCIENCE AND ENGINEERING. THIS PARTNERSHIP WILL ESTABLISH A NEW K-12 TEACHER TRAINING PROGRAM, ENGAGE IN SUMMER ACADEMIC ENRICHMENT PROGRAMS AT XULA, AND BEGIN A NEW COMMUNITY OUTREACH EFFORT ENGAGING THE K-12 COMMUNITY IN MATERIALS SCIENCE THROUGH ART. THIS PROJECT IS PARTIALLY SUPPORTED WITH CO-FUNDING FROM THE ESTABLISHED PROGRAM TO STIMULATE COMPETITIVE RESEARCH (EPSCOR), HBCU-UP PROGRAM IN THE DIVISION OF EQUITY FOR EXCELLENCE IN STEM (EES) IN THE DIRECTORATE FOR STEM EDUCATION (EDU), AND SUSTAINABLE CHEMISTRY FROM THE OFFICE OF STRATEGIC INITIATIVES (OSI) IN THE DIRECTORATE FOR MATHEMATICAL AND PHYSICAL SCIENCES (MPS). FACILITATED BY THE XULA-UCHICAGO PREM, THIS PROJECT OFFERS NEWLY ENVISIONED RESEARCH DIRECTIONS THAT ARE FOCUSED ON THE DEVELOPMENT OF INNOVATIVE COMPOSITE MATERIALS THROUGH TWO NEW RESEARCH THRUSTS. RESEARCH THRUST 1 FOCUSES ON UNDERSTANDING THE STRUCTURE-PROPERTY RELATIONSHIPS OF POLYMER-BASED COMPOSITE MATERIALS THAT INCLUDE ORGANIC IONIC PLASTIC CRYSTALS (OIPC). OIPCS ARE AN EMERGING CLASS OF SOFT MATERIAL THAT RESEMBLE IONIC LIQUIDS IN THEIR MOLECULAR STRUC?TURE. THESE UNIQUE ORGANIC SALTS EXHIBIT MULTIPLE ENDOTHERMIC THERMAL TRANSITIONS THAT ARE DUE TO THE ABILITY OF OIPCS TO EXHIBIT BOTH LONG-RANGE CRYSTALLINE ORDER AND SHORT-RANGE DISORDER, RESULTING FROM LOCALIZED ROTATIONAL MOTION OF IONIC SPECIES COMPRISING THE ORGANIC SALT. THE PROPERTIES OF OIPCS ARE RELEVANT TO SOLID-STATE ENERGY STORAGE SYSTEMS, ELECTROCHROMIC DEVICES, AND GAS SEPARATION TECHNOLOGIES. DESPITE THEIR INTRIGUING PROPERTIES, THE STRUCTURE-PROPERTY RELATIONSHIPS OF OIPCS AND THEIR POLYMER COMPOSITES ARE AN UNDERSTUDIED RESEARCH AREA WITHIN MATERIALS SCIENCE. TO CLOSE THIS KNOWLEDGE GAP, RESEARCH THRUST 1 WILL FOCUS ON (1) UNDERSTANDING THE STRUCTURE-PROPERTY RELATIONSHIPS OF NEW OIPCS, AND (2) 3D-PRINTING OF POLYMER/OIPC COMPOSITE MATERIALS. RESEARCH THRUST 2 INVOLVES THE DESIGN AND STUDY OF NEW COMPOSITE MATERIALS THAT SUPPORT SOLID-STATE LITHIUM METAL BATTERIES AND INCLUDES RESEARCH PROJECTS THAT ADDRESS FOUR MAIN OBJECTIVES: (1) SYNTHESIS AND CHARACTERIZATION OF REDOX-ACTIVE BIS(NAPHTHOQUINONES), (2) COMPUTATIONAL MODELING TO DETERMINE THE LITHIUM INTERCALATION MECHANISM IN BIS(NAPHTHOQUINONES), (3) INVESTIGATING THE INTERFACIAL REACTIONS BETWEEN BIS(NAPHTHOQUINONE)-BASED CATHODES AND SOLID POLYMER ELECTROLYTE, AND (4) PREPARING SOLID POLYMER ELECTROLYTE IONOGELS COMPRISED OF A PARTIALLY FLUORINATED POLYMER MATRIX. OVERALL, THE MATERIALS INVESTIGATED WITHIN THRUST 2 ARE EXPECTED TO PROVIDE ROBUST BATTERY CYCLABILITY IN SOLID-STATE LITHIUM METAL BATTERIES, IMPROVE ION TRANSPORT AND ENHANCE THE ELECTRO?CHEMICAL STABILITY OF THE POLYMERIC SOLID ELECTROLYTE. 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.

XAVIER UNIVERSITY OF LOUISIANA-MOBILE OUTREACH FOR LABORATORY ENRICHMENT (XULA-MOLE) - PROJECT SUMMARY THE APPLICATION FOR XAVIER UNIVERSITY OF LOUISIANA'S MOBILE OUTREACH FOR LABORATORY ENRICHMENT (XULA- MOLE) PROPOSES A COMPREHENSIVE TRAINING AND MENTORING PROGRAM FOR HIGH SCHOOL STUDENTS AND TEACHERS. THIS PROJECT IS A PARTNERSHIP BETWEEN XAVIER AND PARTICIPATING LOCAL HIGH SCHOOLS. THE LONG-TERM OBJECTIVE OF THIS COLLABORATION IS TO STIMULATE SCIENCE INTEREST IN HIGH SCHOOL STUDENTS IN THE NEW ORLEANS AREA AS A PRECURSOR TO THEM PURSUING CAREERS IN THE BIOMEDICAL SCIENCES OR STEM FIELDS. THE XULA- MOLE PROJECT ALSO AIMS TO BETTER SUPPORT SCIENCE TEACHERS WITH PEDAGOGICAL AND RESEARCH PROJECT DESIGN TRAINING AND MENTORING TO INCREASE THEIR IMPACT IN THE CLASSROOM. THE INTRODUCTION OF MOBILE INQUIRY-BASED STEM (SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS) CENTERED LABORATORY EXPERIENCES WILL ENCOURAGE HIGH SCHOOL STUDENTS IN THIS RESOURCE POOR SETTING TO PURSUE FURTHER EDUCATION AND CAREERS IN SCIENTIFIC FIELDS. THIS PROGRAM IS ESPECIALLY IMPORTANT TO THE NEW ORLEANS AREA HIGH SCHOOLS, WHICH AFTER HURRICANE KATRINA HAVE STRUGGLED TO FIND SYNERGY BETWEEN CURRICULUM DESIGN AND EDUCATION REFORM IMPLEMENTATION. THE GENERAL STRATEGY FOR THIS PROPOSED WORK WILL BE CARRIED OUT VIA A FOUR-PRONGED APPROACH INVOLVING (I) INQUIRY-BASED LABORATORY EXPERIENCES, (II) PROFESSIONAL DEVELOPMENT AND RESEARCH DESIGN TRAINING FOR TEACHERS, (III) ESTABLISHING NEAR-PEER MENTORING PROGRAMS BETWEEN XAVIER UNDERGRADUATES AND THEIR PRE-COLLEGE PEERS AND (IV) HIGH SCHOOL FIELD TRIPS TO BIOMEDICAL RESEARCH LABS AT XAVIER. THE XULA-MOLE PROJECT PARTICIPANTS INCLUDE XAVIER FACULTY AND UNDERGRADUATE STEM STUDENTS WHO WILL DESIGN INQUIRY-BASED GUIDED LABORATORY MODULES FOR THE PARTICIPATING HIGH SCHOOLS ALIGNED TO THE NGSS SCIENCE PROCESSES. THE SPECIFIC ACTIVITIES FOR XULA-MOLE WILL BE DESIGNED WITH INSPIRATION FROM PREVIOUS SEPA-FUNDED PROGRAMS SUCH AS BEST SCIENCE!, WHICH FOCUSED ON PROFESSIONAL DEVELOPMENT WORKSHOPS FOR TEACHERS, AND THE LONG-SUSTAINING CITYLAB, WHICH MOST RECENTLY IS PILOTING AN AFTER SCHOOL SCIENCE EDUCATION PROGRAM IMPACTING STUDENTS' SCIENCE IDENTITY. BY USING A MULTI-PRONGED STRATEGY TO INSPIRE SCIENCE TEACHING AND LEARNING, THE XULA-MOLE PROGRAM AIMS TO DEVELOP A MODEL SYSTEM THAT CAN BE APPLIED TO MULTIPLE SCHOOLS AND GRADE LEVELS.

CAMPUS BASED-FWS

CAMPUS BASED-FWS

XAVIER UNIVERSITY OF LOUISIANA - MCNAIR SCHOLARS PROGRAM

STRENGTHENING PROGRAMMING AT XAVIER UNIVERSITY OF LOUISIANA

XAVIER UNIVERSITY OF LOUISIANA REACHES THE UNDERREPRESENTED IN BIOMEDICAL RESEARCH (XULA RUBR) - NO ABSTRACT

EXCELLENCE IN RESEARCH: MOLECULAR CHARACTERIZATION OF THE TLE1-MEDIATED TRANSCRIPTIONAL AND EPIGENETIC PROGRAM AS A MODULATOR OF EPITHELIAL CELL SURVIVAL AND A TARGET OF INTEGRINS -CELLS ON THE SURFACE OF ANIMAL TISSUES AND ORGANS ADHERE FOR SURVIVAL TO AN UNDERLYING EXTRACELLULAR MATRIX (ECM) OF PROTEINS VIA ADHESION PROTEINS CALLED INTEGRINS. LOSS OF CELL ATTACHMENT IS REGULATED TO SHED CELLS FROM THESE TISSUES VIA A PROCESS CALLED PROGRAMMED CELL DEATH. WHILE DIRECT INTEGRIN-MEDIATED SIGNALS TO DOWNSTREAM CELL DEATH PROCESSES ARE WELL CHARACTERIZED, LITTLE IS KNOWN ABOUT OTHER INTEGRIN-REGULATED MECHANISMS THAT AFFECT OR PREVENT PROGRAMMED CELL DEATH. THIS PROJECT AIMS TO UNDERSTAND THE ROLE OF AN INTEGRIN-MEDIATED PROTEIN CALLED TLE1, WHICH WORKS AS A MASTER REGULATOR OF INTEGRIN-MEDIATED CELL SURVIVAL VIA TLE1?S EFFECTS ON ACTIVATION OF MANY GENES. THE RESEARCH PLAN IS TO CHARACTERIZE THESE DOWNSTREAM GENE TARGETS OF TLE1, AS WELL AS COMPONENTS OF THE OTHER PROTEINS THAT WORK WITH TLE1 IN ORDER TO BETTER UNDERSTAND THE REGULATION OF THE BALANCE BETWEEN CELL SURVIVAL AND DEATH, WHICH IS ESSENTIAL FOR DEVELOPMENT AND MAINTENANCE OF ORGANISMS. BY ADVANCING KNOWLEDGE OF THE REGULATION OF CELL DEATH, THIS PROJECT MAY YIELD NOVEL THERAPEUTIC STRATEGIES THAT TARGET CELL DEATH PATHWAYS IN ORDER TO ADVANCE OR PREVENT REMOVAL OF CELLS FOR DISEASE TREATMENT. ADDITIONALLY, THIS PROJECT EXPANDS THE RESEARCH CAPABILITY AT XAVIER UNIVERSITY OF LOUISIANA AND SUPPORTS EDUCATION AND BROADENING PARTICIPATION FOR UNDERGRADUATE STUDENTS BY INTEGRATING SYSTEMS BIOLOGY RESEARCH INTO UNDERGRADUATE COURSES AND PROVIDING RESEARCH OPPORTUNITIES FOR UNDERGRADUATE STUDENTS. THE PROJECT WILL GENERATE CRUCIAL INSIGHTS INTO THE TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS GOVERNING EPITHELIAL CELL SURVIVAL. SPECIFICALLY, IT WILL EXPLORE THE ROLE OF TRANSCRIPTIONAL COREGULATORS AS MOLECULAR TARGETS OF INTEGRINS IN FINE-TUNING EPIGENETIC AND TRANSCRIPTIONAL RESPONSES. USING MULTIOMICS AND BIOINFORMATIC APPROACHES, THIS PROJECT AIMS TO: I) IDENTIFY THE SURVIVAL-PROMOTING GENE TRANSCRIPTIONAL PROGRAM CONTROLLED BY TLE1 AND INTEGRIN-REGULATED CELL ADHESION VIA INTEGRATED RNA-SEQ AND CHIP-SEQ ANALYSIS; II) CHARACTERIZE THE KEY COMPONENTS OF THE TLE1 COREPRESSOR COMPLEX THAT DRIVE TRANSCRIPTIONAL AND EPIGENETICS EVENTS UNDERPINNING EPITHELIAL CELL SURVIVAL THROUGH PROTEOMICS; AND III) MAP THE TLE1-DEPENDENT GENOME-WIDE HISTONE MARKS ASSOCIATED WITH EPITHELIAL CELL SURVIVAL BY USE OF EPIGENETIC AND EPIGENOMIC APPROACHES. LEVERAGING INTEGRATED MULTIOMICS DATA ANALYSIS COUPLED WITH MOLECULAR, BIOCHEMICAL, AND CELLULAR VALIDATION, THIS PROJECT WILL UNDERSCORE THE ROLE OF TLE1 IN DEFINING AN EPIGENETIC SIGNATURE PERMISSIVE OF GENE EXPRESSION CRITICAL FOR ADHESION-DEPENDENT CELL SURVIVAL. INHIBITION OF TLE1?S NUCLEAR FUNCTION UPON LOSS OF INTEGRIN-DEPENDENT SURVIVAL SIGNAL MAY RESULT IN AN EPIGENOMIC LANDSCAPE ASSOCIATED WITH CELL DEATH. THE RESEARCH FINDINGS WILL PROVIDE A MECHANISTIC FRAMEWORK FOR THE ROLE OF TRANSCRIPTIONAL COREGULATORS IN LINKING EPIGENOME ALTERATIONS TO TRANSCRIPTIONAL REPROGRAMMING DURING CELLULAR STRESS. THIS WORK WILL ALSO HAVE SIGNIFICANT IMPACT ON UNDERSTANDING ANIMAL TISSUE HOMEOSTASIS AND ORGANISMAL DEVELOPMENT, AS BOTH PROCESSES REQUIRE PRECISE REGULATION OF EPITHELIAL CELL SURVIVAL AND DEATH. 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.

XAVIER-UCHICAGO PARTNERSHIP FOR RESEARCH AND EDUCATION IN MATERIALS FOR ENERGY STORAGE AND SENSING

REGULATION AND LOCALIZATION OF MISMATCH REPAIR PROTEINS - PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR (LAST, FIRST, MIDDLE): HAYE, JOANNA, ELIZABETH ABSTRACT: DNA MISMATCH REPAIR (MMR) IS A HIGHLY CONSERVED PROCESS. A FUNCTIONAL MMR PATHWAY IS ESSENTIAL FOR MAINTAINING GENOME INTEGRITY; LOSS OF MMR RESULTS IN GENOME INSTABILITY AND CANCER IN HIGHER EUKARYOTES. FOR EXAMPLE, DEFECTS IN MMR GENES RESULT IN LYNCH SYNDROME, A COMMON HEREDITARY CANCER SYNDROME RESULTING IN EARLY ONSET CANCERS OF THE COLON, ENDOMETRIUM, OVARIES, SMALL INTESTINE, HEPATOBILIARY TRACT, UPPER URINARY TRACT AS WELL AS OTHER TISSUES. IN OUR MOST RECENT PUBLICATION, WE SHOWED THAT IN YEAST, DELETION OF MODULATOR OF TRANSCRIPTION (ALSO KNOWN AS NOT4) OR GENERAL CONTROL NONDEREPRESSIBLE 5 (GCN5) MODULATE THE LEVELS OF MSH2, A MAJOR MMR COMPONENT. LOSS OF GCN5 SIGNIFICANTLY DECREASES MSH2, WHEREAS DELETING NOT4 STABILIZES FUNCTIONAL MSH2. NOT4 AND GCN5 ARE PROTEINS THAT UBIQUITYLATE AND ACETYLATE VARIOUS PROTEINS RESPECTIVELY. WE HYPOTHESIZE THAT NOT4 AND GCN5 MODIFY YEAST MUTSA (COMPRISED OF MS2 AND MSH6) AND THAT THE MODIFICATIONS AFFECT THE STABILITY OF THE COMPLEX. USING THE YEAST SACCHAROMYCES CEREVISIAE (S. CEREVISIAE), THE FIRST AIM OF THE PROPOSED RESEARCH IS TO ESTABLISH THE ROLE OF GCN5 AND NOT4 IN THE REGULATION OF THE MAJOR MISMATCH RECOGNITION COMPLEX MUTSA. OUR PREVIOUS EXPERIMENTS HAVE ALSO SHOWN THAT YEAST MUTS TRACKS WITH THE REPLICATION MACHINERY DURING DNA REPLICATION. HUMAN MUTSA IS RECRUITED TO CHROMATIN THROUGH SPECIFIC HISTONE MODIFICATIONS AND INTERACTS WITH THE REPLICATION MACHINERY BY BINDING PCNA, THE DNA POLYMERASE PROCESSIVITY FACTOR. HOWEVER, THE MODIFICATIONS THAT RECRUIT HUMAN MUTSA ARE NOT UTILIZED IN YEAST. HOW YEAST MUTSA IS RECRUITED TO CHROMATIN REMAINS ELUSIVE. THE SECOND AIM OF THIS RESEARCH IS TO DETERMINE THE ROLE OF POST- TRANSLATIONAL MODIFICATIONS IN MUTSA RECRUITMENT TO CHROMATIN. PHS398 (REV. 5/01) PAGE CONTINUATION FORMAT PAGE

IRREVERSIBLE ESTROGEN RECEPTOR INHIBITORS - PROJECT SUMMARY CONSTITUTIVELY ACTIVE SOMATIC MUTATIONS IN THE ESTROGEN RECEPTOR (ER) LIGAND BINDING DOMAIN (LBD) HAVE EMERGED AS A FREQUENT MECHANISM OF ENDOCRINE THERAPY RESISTANCE IN PATIENTS WITH METASTATIC ER+ BREAST CANCERS. UNFORTUNATELY, THERE ARE NO THERAPEUTIC AGENTS TO ADDRESS THIS PATIENT POPULATION. THE LONG-TERM GOAL IS TO DEVELOP THERAPEUTICALLY USEFUL IRREVERSIBLE ER INHIBITORS FOR THE TREATMENT OF ER+ METASTATIC BREAST CANCER, WHICH WILL CREATE THERAPY OPTIONS FOR INDIVIDUALS WHO HAVE FAILED OR RELAPSED ON CURRENT THERAPIES. THE OVERALL OBJECTIVE IS TO IDENTIFY TEMPLATE-BASED IRREVERSIBLE ER INHIBITORS THAT CAN BIND TO THE ER WITH HIGH AFFINITY AND FORM AN IRREVERSIBLE COVALENT C-S BOND WITH THE C530 AMINO ACID RESIDUE IN THE ER LBD. THE CENTRAL HYPOTHESIS IS THAT A PHARMACEUTICALLY OPTIMIZED IRREVERSIBLE ER INHIBITOR CAN BE OBTAINED BY INCORPORATING CLINICALLY PROVEN ER- BINDING MOTIFS AND A COVALENT-BOND FORMING MICHAEL ADDITION MOIETY IN THE MOLECULES. THIS HYPOTHESIS IS SUPPORTED BY EARLY TRIPHENYLETHYLENE-BASED IRREVERSIBLE ER ANTAGONISTS EXHIBITING UTEROTROPHIC EFFECTS SIMILAR TO TAMOXIFEN, AND PROTOTYPE COMPOUNDS FROM OUR LABORATORY WITH THIOPHENE (RALOXIFENE-LIKE) CORE DEMONSTRATING LACK OF SUCH EFFECT BUT EQUALLY POTENT ANTAGONISM IN THE BREAST. THE CENTRAL HYPOTHESIS WILL BE TESTED BY PURSUING THREE SPECIFIC AIMS: 1) DESIGN AND SYNTHESIS OF IRREVERSIBLE ER INHIBITORS; 2) DETERMINE THE IMPACT OF THE IRREVERSIBLE ER INHIBITORS ON PROLIFERATION IN BREAST CANCER CELLS, AND 3) EVALUATE IN VIVO PHARMACODYNAMICS AND ANTI-TUMOR THERAPEUTIC EFFICACY OF NOVEL IRREVERSIBLE ER INHIBITORS. UNDER THE FIRST AIM, IRREVERSIBLE ER BINDING INHIBITORS WILL BE SYNTHESIZED USING CORES MOTIFS: TRIPHENYLETHYLENES (TAMOXIFEN-LIKE) AND BENZOTHIOPHENES (RALOXIFENE-LIKE) AND ARE EXPECTED TO BE HIGHLY SELECTIVE, POTENT, AND TO EXERT PERMANENT ANTAGONISM. UNDER AIM TWO, THE SYNTHESIZED COMPOUNDS WILL BE EVALUATED IN THEIR ABILITY TO FORM A COVALENT BOND WITH ER C530 AND INHIBIT THE GROWTH OF BREAST CANCER CELLS. FOR THE THIRD AIM, THE LEAD AGENT FROM EACH STRUCTURAL MOTIF GROUP WILL BE IDENTIFIED FOR FURTHER PRECLINICAL STUDIES AND EFFICACY IN PATIENT-DERIVED XENOGRAFT BREAST TUMOR MODELS. THE RESEARCH HERE IS INNOVATIVE BECAUSE IT FOCUSES ON THE USE OF IRREVERSIBLE INHIBITORS TO OVERCOME ENDOCRINE RESISTANCE AND INCORPORATES NOVEL MOIETIES TO ACHIEVE HIGH DRUG EXPOSURE. THIS CONTRIBUTION IS SIGNIFICANT BECAUSE IT WILL IDENTIFY A CLASS OF IRREVERSIBLE ER INHIBITORS THAT DISPLAY NOVEL ANTIESTROGENIC EFFECTS, LACKS AGONIST ACTIVITIES, AND HAS HIGH ORAL BIOAVAILABILITY, OFFERING NEW OPPORTUNITIES FOR THE DEVELOPMENT OF INNOVATIVE THERAPIES TO TREAT BREAST CANCER.

RUI: MAPPING LYSINE DEACETYLASE SUBSTRATE SELECTIVITY -THE GOAL OF THIS RESEARCH PROJECT IS TO UNDERSTAND HOW A GROUP OF ENZYMES, NAMELY LYSINE DEACETYLASES, CONTROL BIOLOGICAL PROCESSES IN CELLS. THIS PROJECT WILL ALSO PROVIDE EXPERIMENTAL APPROACHES THAT CAN BE APPLIED TO RELATED AVENUES OF RESEARCH, WITH SUBSEQUENT IMPACT ON UNDERSTANDING OF FUNDAMENTAL BIOLOGY AND MEDICINE. THE ACTIVITIES IN THIS PROJECT WILL BE PERFORMED PRIMARILY BY UNDERGRADUATE STUDENTS AND RECENT GRADUATES FROM UNDERREPRESENTED GROUPS IN SCIENTIFIC FIELDS. STUDENTS AND RECENT GRADUATE TECHNICIANS WILL GAIN MEANINGFUL RESEARCH SKILLS AND TRAINING RELEVANT FOR PROGRESSION INTO GRADUATE PROGRAMS AND THE SCIENTIFIC WORKFORCE. LYSINE DEACETYLASES (KDACS OR HDACS) ARE A FAMILY OF CLOSELY RELATED ENZYMES THAT REGULATE POST-TRANSLATIONAL ACETYLATION OF PROTEINS THROUGH REMOVAL OF ACETYL GROUPS FROM LYSINE RESIDUES. THE OVERALL GOAL OF THIS RESEARCH IS TO UNDERSTAND HOW FOUR KDACS REGULATE CELLULAR ACTIVITY, BY (1) IDENTIFYING THE MOLECULAR INTERACTIONS OF KDACS THAT DETERMINE SUBSTRATE SELECTIVITY, AND (2) IDENTIFYING THE SPECIFIC KDAC RESPONSIBLE FOR DEACETYLATION OF PARTICULAR ACETYLATED LYSINE RESIDUES IN NON-HISTONE PROTEINS. A COMBINATION OF IN VITRO ACTIVITY ASSAYS, MOLECULAR DYNAMICS SIMULATIONS, AND A CELL-BASED APPROACH INVOLVING GENETICALLY ENCODED BUT CATALYTICALLY INACTIVE KDACS WILL LEAD TO IDENTIFICATION OF CELLULAR SUBSTRATES AND A DETAILED UNDERSTANDING OF THE PARTICULAR MOLECULAR INTERACTIONS DRIVING ACTIVITY BETWEEN A SPECIFIC KDAC AND THE ACETYLATED PROTEIN. OVERALL, THE PROJECT WILL RESULT IN A PHYSICAL MAP OF THE SURFACE OF EACH KDAC THAT DETERMINES SELECTIVITY, AS WELL AS DEFINITIVE SUBSTRATE IDENTIFICATION LEADING TO A CONCEPTUAL MAP OF THE CELLULAR PROCESSES CONTROLLED BY THE KDACS VIA THEIR SUBSTRATES. THIS PROJECT IS JOINTLY FUNDED BY THE MOLECULAR BIOPHYSICS CLUSTER IN THE DIVISION OF MOLECULAR AND CELLULAR BIOSCIENCES (MCB) AND THE ESTABLISHED PROGRAM TO STIMULATE COMPETITIVE RESEARCH (EPSCOR). 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.

EXCELLENCE IN RESEARCH: MOLECULAR-LEVEL INVESTIGATIONS ON BINARY IMIDAZOLIUM-BASED IONIC LIQUIDS MIXTURE -WITH SUPPORT FROM THE CHEMICAL STRUCTURE AND DYNAMICS (CSD) PROGRAM IN THE DIVISION OF CHEMISTRY AND THE HISTORICALLY BLACK COLLEGES AND UNIVERSITIES EXCELLENCE IN RESEARCH (HBCU-EIR) PROGRAM IN THE OFFICE OF INTEGRATIVE ACTIVITIES, PROFESSORS SAMRAT DUTTA AND KEVIN RILEY, OF XAVIER UNIVERSITY OF LOUISIANA WILL STUDY THE CONNECTION BETWEEN IONIC LIQUID STRUCTURES AND THEIR RESULTING MACROSCOPIC PROPERTIES (SUCH AS VISCOSITY AND GAS SOLUBILITY) IN MIXTURES. WHILE SINGLE IONIC LIQUIDS HAVE BEEN PURSUED AS A PROMISING CLASS OF ENVIRONMENTALLY FRIENDLY SOLVENTS BOTH FOR INDUSTRIAL AND LABORATORY PRACTICES, LITTLE IS KNOWN ABOUT THE BEHAVIOR OF MIXTURES OF IONIC LIQUIDS AND HOW SUCH MIXING IMPACTS THEIR PROPERTIES. MIXTURES OF IONIC LIQUIDS POSSESS UNIQUELY HIGH GAS SOLUBILITY AS COMPARED TO THEIR PURE COUNTERPARTS AND CAN BE POLYMERIZED TO FORM INTERFACES FOR SOLID-STATE ION TRANSPORT WHICH ARE ALSO INFLUENCED BY THEIR MIXING ABILITY. THE TEAM WILL DEVELOP UNIQUE VIBRATIONAL SPECTROSCOPY PROBES, SUPPORTED BY QUANTUM CHEMISTRY CALCULATIONS, TO PRESENT A MOLECULAR PICTURE OF IONIC LIQUID MIXTURES, PARTICULARLY FROM THE PERSPECTIVE OF IDEALITY OF MIXING. A DEEPER UNDERSTANDING OF IONIC LIQUID SOLUTIONS WILL ENABLE THE DEVELOPMENT OF MIXED SOLVENTS WITH PREDICTABLE PROPERTIES TO FACILITATE PRACTICAL APPLICATIONS, SUCH AS POST-COMBUSTION CARBON CAPTURE. THE ACTIVITIES IN THE PROJECT WILL BROADEN UNDERREPRESENTED UNDERGRADUATE SCHOLARS? PARTICIPATION IN THE NATION'S STEM WORKFORCE SPECIFICALLY IN THE EMERGING GLOBAL IONIC LIQUID INDUSTRY. THE MICROENVIRONMENT OF IMIDAZOLIUM-BASED BINARY IONIC LIQUID MIXTURES, WHICH ARE ENTIRELY MADE OF IONS, ARE COMPLICATED BY MANY COMPETITIVE FORCES INCLUDING, BUT NOT LIMITED TO, COULOMB FORCES, HYDROGEN BONDING, AND DISPERSION INTERACTIONS. UNDERSTANDING THE MICROENVIRONMENT OF THESE COMPLEX SOLVENTS CAN ENABLE THE DEVELOPMENT OF BETTER IONIC LIQUID MIXTURES WITH PREDICTABLE PROPERTIES. TO THIS END, THE RESEARCH WILL STUDY THE MICROENVIRONMENT OF BINARY MIXTURES OF IONIC LIQUIDS, EXAMINE GAS-IONIC LIQUID INTERACTIONS IN SUCH MIXTURES UNDER DIFFERENT CONDITIONS, AND ANALYZE THE NATURE OF THE INTERPHASE BETWEEN TWO IONIC LIQUIDS WHEN POLYMERIZED AND LAMINATED TOGETHER IN THE SOLID STATE. A VARIETY OF FOURIER-TRANSFORM INFRARED SPECTROSCOPY (FT-IR) TECHNIQUES WILL BE LEVERAGED TO STUDY THESE SYSTEMS INCLUDING TWO-DIMENSIONAL (2D-IR) SPECTROSCOPY AND INFRARED MICROSCOPY, ALONG WITH DENSITY FUNCTIONAL THEORY (DFT) AND MOLECULAR DYNAMICS (MD) SIMULATION. THE PROPOSAL WILL PROVIDE A SPECTROSCOPIC TOOL KIT VIA A C-D VIBRATIONAL LABEL ON THE IMIDAZOLIUM CATION TO INTERROGATE THE STRUCTURE AND DYNAMICS OF THE BINARY IONIC LIQUID MIXTURE. THE OUTCOMES OF THIS WORK WILL INCLUDE METHODS TO DISTINGUISH BETWEEN IDEAL AND NON-IDEAL BINARY MIXTURES, INSIGHTS INTO DISSOLUTION MECHANISMS OF GASES IN BINARY MIXTURES, AND EVIDENCE OF MIGRATION OF IONS BETWEEN TWO POLYMERIZED IONIC LIQUIDS. ON A BROAD SCALE, THE PROJECT WILL PROVIDE A PLATFORM FOR YOUNG, UNDERREPRESENTED UNDERGRADUATE STUDENTS TO BE ENGAGED IN NATIONALLY COMPETITIVE RESEARCH, PREPARE THEM FOR GRADUATE RESEARCH, AND PROVIDE OPPORTUNITIES FOR LEADERSHIP IN STEM AREAS. 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.

INHIBITORS OF HUMAN FACTOR XIIIA AS NEW ANTICOAGULANTS - SUMMARY THE LONG-TERM GOAL OF OUR RESEARCH IS TO DEVELOP EFFECTIVE ANTICOAGULANTS THAT DO NOT CAUSE BLEEDING COMPLICATIONS TO BE SAFELY USED FOR A WIDER RANGE OF PATIENTS SUFFERING FROM VENOUS THROMBOEMBOLISM (VTE). THIS PROJECT AIMS AT DEVELOPING EFFECTIVE AND SAFER ANTICOAGULANTS BY TARGETING HUMAN FACTOR XIIIA (FXIIIA). ALL AVAILABLE ANTICOAGULANTS ARE ASSOCIATED WITH A SIGNIFICANT RISK OF BLEEDING. CURRENT ANTICOAGULANTS INHIBIT DIRECTLY OR INDIRECTLY THROMBIN AND/OR FACTOR XA. THIS IS THE REASON WHY THEY ARE CLINICALLY EFFECTIVE, BUT IT IS ALSO THE REASON WHY THEY CAUSE BLEEDING. THE CENTRAL HYPOTHESIS IS THAT INHIBITING FXIIIA WILL RESULT IN EFFECTIVE PROTECTION AGAINST VTE WITHOUT CAUSING SIGNIFICANT BLEEDING. IN CONTRAST TO ALL OTHER CLOTTING FACTORS WHICH ARE SERINE PROTEASES, FXIIIA IS A TRANSGLUTAMINASE THAT CATALYZES THE LAST STEP IN THE COAGULATION PROCESS. THIS UNIQUE BIOCHEMICAL ASPECT OF FXIIIA HAS BEEN UNDER INVESTIGATION IN THE CONTEXT OF VTE. IN VITRO EXPERIMENTS SHOWED THAT TREATING NORMAL HUMAN BLOOD WITH AN EXPERIMENTAL TRANSGLUTAMINASE INHIBITOR INCREASES RBC EXTRUSION FROM CONTRACTING CLOTS AND REDUCES CLOT SIZE. VARIOUS STUDIES ALSO SUGGESTED THAT A CERTAIN FXIIIA POLYMORPHISM PROVIDES SIGNIFICANT PROTECTION AGAINST VTE AND THAT HETEROZYGOUS FXIII-DEFICIENT MICE DO NOT SHOW SIGNS OF EXCESSIVE BLEEDING. THUS, FXIIIA MAY SERVE AS A POTENTIAL THERAPEUTIC TARGET TO DEVELOP A NEW EFFECTIVE TREATMENT FOR VTE THAT DOES NOT SIGNIFICANTLY INCREASE THE BLEEDING RISK. DESPITE THIS PROMISE, VERY FEW FXIIIA INHIBITORS HAVE BEEN DEVELOPED, ALL OF WHICH LACK SUBSTANTIAL SELECTIVITY AS THEY CAN ALSO INHIBIT OTHER TRANSGLUTAMINASES BY BLOCKING THEIR ACTIVE SITES. THUS, I HAVE PROPOSED SULFONATED NON-SACCHARIDE GLYCOS- AMINOGLYCAN MIMETICS AS A PLATFORM TO DEVELOP FXIIIA INHIBITORS. THE SULFONATED MOLECULES ARE TO INHIBIT FXIIIA POTENTLY AND SELECTIVELY THROUGH ALLOSTERIC MODULATION. IN PRELIMINARY STUDIES, I DISCOVERED TWO SULFONATED MOLECULES THAT INHIBIT FXIIIA WITH LOW MICROMOLAR POTENCIES. THE TWO MOLECULES INHIBITED FXIIIA-MEDIATED POLYMERIZATION OF FIBRIN. THE TWO MOLECULES DID NOT AFFECT OTHER CLOTTING FACTORS AND DID NOT AFFECT THE VIABILITY OF THREE CELL LINES. MOLECULAR MODELING PROJECTED A PLAUSIBLE BINDING SITE FOR THESE MOLECULES ON FXIIIA. IN THIS PROPOSAL, I SPECIFICALLY AIM AT USING A MULTIDISCIPLINARY APPROACH TO ESTABLISH THE PRINCIPLES OF EFFECTIVE AND SELECTIVE INHIBITION OF FXIIIA BY SULFONATED MOLECULES. I WILL SYNTHESIZE ADVANCED LIBRARIES OF TWO “LEAD” MOLECULES AND EVALUATE THEIR BIOCHEMICAL AND BIOLOGICAL POTENTIAL AS ANTICOAGULANTS. THE PROPOSAL IS INNOVATIVE BECAUSE I) IT PUTS FORWARD A NOVEL APPROACH TO OVERCOME THE LIMITATIONS OF CURRENT VTE TREATMENT; II) IT EXPLOITS A MULTIDISCIPLINARY APPROACH TO INVESTIGATE THE SPECIFIC AIMS; AND III) IT INTRODUCES NEW TECHNOLOGIES WITH PROPRIETARY STRUCTURAL AND MECHANISTIC ASPECTS. THE PROJECT IS ALSO SIGNIFICANT BECAUSE IT WILL: I) IDENTIFY 2-3 POTENT, SPECIFIC, AND ALLOSTERIC FXIIIA INHIBITORS FOR FUTURE EVALUATION IN ANIMAL MODELS OF VTE AND BLEEDING; II) OFFER NEW TOOLS TO BETTER UNDERSTAND FXIIIA ROLE IN THE COAGULATION PHYSIOLOGY AND PATHOLOGY; III) INVESTIGATE AN ALTERNATIVE APPROACH TO MODULATE FXIIIA VIA ALLOSTERY TO PAVE THE WAY TO TRANSFORMING ANTICOAGULANTS.

CAMPUS BASED-FSEOG

ROLE OF THE TRANSCRIPTIONAL COREPRESSOR TLE1 IN THE LUNG ADENOCARCINOMA AGGRESSIVENESS AND PROGRESSION - PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR (LAST, FIRST, MIDDLE): BILIRAN JR., HECTOR ROLE OF THE TRANSCRIPTIONAL COREPRESSOR TLE1 IN THE LUNG ADENOCARCINOMA AGGRESSIVENESS AND PROGRESSION ABSTRACT LUNG ADENOCARCINOMA (LUAD), WHICH ACCOUNTS FOR ALMOST 40% OF LUNG CANCER, HAS A 5-YEAR SURVIVAL RATE OF ONLY 15% DUE TO ITS AGGRESSIVE BEHAVIOR. HENCE, THERE IS AN URGENT NEED TO BETTER UNDERSTAND THE MOLECULAR EVENTS UNDERLYING THE DEVELOPMENT AND PROGRESSION OF LUAD. THIS LAB'S PRIOR R15 WORK HAS OBTAINED EVIDENCE THAT THE TRANSCRIPTIONAL COREPRESSOR TLE1 EXERTS AN ANTI-APOPTOTIC- AND EMT-PROMOTING FUNCTION IN LUAD CELLS AND THEREBY POTENTIATING THEIR ANOIKIS RESISTANCE, AND ANCHORAGE-INDEPENDENT GROWTH IN VITRO AS WELL AS TUMORIGENESIS IN VIVO. MECHANISTICALLY, THE DUAL SURVIVAL- AND EMT-PROMOTING FUNCTION OF TLE1 IS IN PART DUE TO ITS TRANSCRIPTIONAL SILENCING OF THE TUMOR SUPPRESSOR E-CADHERIN GENE VIA THE TRANSCRIPTION FACTOR ZEB1 AND CHROMATIN MODIFYING ENZYME HISTONE DEACETYLASE (HDAC). OUR RECENT BIOINFORMATICS ANALYSES INDICATE THAT TLE1 IS UPREGULATED AND DISPLAYS A POOR PROGNOSTIC VALUE IN LUAD. BASED ON THESE COLLECTIVE DATA, WE HYPOTHESIZE THAT TLE1 REGULATES A SURVIVAL- AND EMT-PROMOTING GENE TRANSCRIPTION PROGRAM TO DRIVE THE AGGRESSIVENESS AND PROGRESSION OF LUAD. TO TEST THIS HYPOTHESIS, THE FOLLOWING SPECIFIC AIMS WILL BE ADDRESSED: 1) EVALUATE THE FUNCTIONAL ROLE OF TLE1 IN LUAD TUMORIGENESIS AND AGGRESSIVENESS; 2) MOLECULARLY CHARACTERIZE THE COMPONENTS OF THE TLE1-MEDIATED TRANSCRIPTIONAL PROGRAM THAT MAY DRIVE LUAD PROGRESSION; AND 3) DETERMINE WHETHER TLE1 NUCLEAR FUNCTION REGULATES TUMORIGENICITY AND METASTASIS IN LUAD MOUSE XENOGRAFT MODELS. THESE PROPOSED STUDIES, WHICH WILL BE PERFORMED BY UNDERGRADUATE RESEARCH STUDENTS TOGETHER WITH THE PI AND A RESEARCH ASSISTANT, WILL ADVANCE OUR UNDERSTANDING OF THE TLE1 TRANSCRIPTIONAL NETWORK AS A “DRIVER” OF LUAD ONCOGENESIS AND AS A MOLECULAR THERAPEUTIC TARGET TO CURTAIL LUAD AGGRESSIVENESS. PHS398 (REV. 5/01) PAGE CONTINUATION FORMAT PAGE

21-IPMSI21-0023 XULA SURFACE-BASED MEASUREMENT INITIATIVE FOR ENVIRONMENTAL/AIR QUALITY MONITORING

REU SITE: NATURAL AND SYNTHETIC MECHANISMS THAT ALTER BIOLOGICAL PROCESSES -THIS REU SITE AWARD TO XAVIER UNIVERSITY OF LOUISIANA, LOCATED IN NEW ORLEANS, LA WILL SUPPORT THE TRAINING OF 30 STUDENTS FOR 10 WEEKS DURING THE SUMMERS OF 2027-2029. PARTICIPANTS WILL BE RECRUITED FROM ACROSS THE US AND WILL INCLUDE STUDENTS WITH LIMITED ACCESS TO RESEARCH OPPORTUNITIES AND RESOURCES IN THEIR HOME INSTITUTIONS. RESEARCH MENTORS WILL GUIDE TRAINEES IN INDIVIDUAL PROJECTS, ALIGNED WITH THE PROGRAM THEME OF ?NATURAL AND SYNTHETIC MECHANISMS THAT ALTER BIOLOGICAL PROCESSES?, USING AN INTERDISCIPLINARY APPROACH TO PROVIDE CRITICAL INSIGHTS THAT BUILD GREATER UNDERSTANDING OF THE PHYSICAL WORLD. TRAINEES WILL ALSO BE INVOLVED IN COLLABORATIVE RESEARCH AS LABORATORIES WORK TOGETHER TO ADDRESS COMMON INTERESTS AND RESEARCH PROBLEMS. TRAINEES WILL PRESENT THEIR RESEARCH AT AN END-OF-SUMMER SYMPOSIUM AND WILL BE ENCOURAGED TO PRESENT AT NATIONAL SCIENTIFIC CONFERENCES. THROUGHOUT THE SUMMER PROGRAM, THE COHORT OF TRAINEES WILL PARTICIPATE IN SEMINARS AND WORKSHOPS DESIGNED TO ENHANCE PROFESSIONAL SKILLS AND EXPLORE POTENTIAL CAREER PATHS IN THE STEM FIELDS. ASSESSMENT OF THIS PROGRAM WILL BE DONE THROUGH SURVEYS OF TRAINEES AND MENTORS, AS WELL AS THROUGH LONG-TERM TRACKING OF TRAINEE ACADEMIC AND CAREER PATHWAYS AFTER PROGRAM PARTICIPATION. STUDENTS SHOULD APPLY TO THE REU SITE USING NSF ETAP (EDUCATION AND TRAINING APPLICATION: HTTPS://ETAP.NSF.GOV/AWARD/8501/OPPORTUNITY/11970). THE TRAINING STUDENTS WILL RECEIVE IS ALIGNED WITH THE NSF PRIORITY IN BIOTECHNOLOGY. THE MODIFICATION OF BIOLOGICAL ACTIVITY THROUGH CHANGES IN GENETIC CONTENT OR VIA THE ADDITION OF CHEMICAL COMPOUNDS IS THE OVERARCHING THEME OF THIS PROGRAM. THE PROGRAM TAKES A HOLISTIC APPROACH TO STUDYING THE EFFECT OF CHEMICAL AGENTS ON MACROMOLECULES, WITH PARTICULAR EMPHASIS ON MOLECULAR REGULATION, MAINTENANCE OF BIOLOGICAL INTEGRITY, AND CELLULAR COMMUNICATION CRITICAL TO BIOLOGICAL ACTIVITY. BY INTEGRATING RESEARCH LABORATORIES IN THE DEPARTMENTS OF BIOLOGY, CHEMISTRY, NEUROSCIENCE, AND COMPUTER SCIENCE, STUDENTS WILL UTILIZE A WIDE ARRAY OF EXPERIMENTAL METHODOLOGIES TO BETTER UNDERSTAND THE MECHANISMS OF FUNDAMENTAL BIOLOGICAL PROCESSES. FROM MODELING-BASED DESIGN OF MACROMOLECULES TO MOLECULAR SYNTHESIS AND THE SUBSEQUENT TESTING OF COMPOUNDS ON BIOLOGICAL ACTIVITY, TRAINEES WILL GAIN A WEALTH OF SCIENTIFIC KNOWLEDGE AND EXPERIENCE WITH EXPERIMENTAL METHODOLOGY THAT WILL PREPARE THEM FOR FUTURE TRAINING FOR PATHS IN STEM CAREERS. THIS PREPARATION WILL ALSO INVOLVE PROFESSIONAL DEVELOPMENT ACTIVITIES, INCLUDING GRADUATE SCHOOL APPLICATION AND GRE PREP, SCIENCE COMMUNICATION TRAINING, CAREER EXPLORATION SESSIONS, AND VISITS WITH INDUSTRY LEADERS AT A LOCAL BIOINNOVATION CENTER. 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.

EXCELLENCE IN RESEARCH: SPECTROELECTROCHEMICAL MEASUREMENTS ON INTACT MICROORGANISMS UNDER OXIC AND ANOXIC CONDITIONS

FORMULATION OF A TARGETED NANOPARTICLE SYSTEM FOR THE TREATMENT OF CHEMORESISTANT BREAST CANCER - ABSTRACT THE DEVELOPMENT OF MULTIDRUG RESISTANCE (MDR) IN CANCER CELLS IS OF GRAVE CONCERN, LIMITING THE EFFICACY OF ANTICANCER AGENTS AND, HENCE, THE FAILURE OF BREAST CANCER THERAPY. CLINICAL RESEARCH AND APPLICATION REVEALED THAT IN SPITE OF ITS POTENTIAL ANTICANCER EFFECTS, DOXORUBICIN IS HIGHLY TOXIC, AND ITS LONG-TERM APPLICATION MAY CAUSE DOSE-DEPENDENT IRREVERSIBLE CARDIOMYOPATHY, SEVERE CARDIAC TOXICITY, OR LIVER DAMAGE, THEREBY LIMITING ITS APPLICATION IN BREAST CANCER TREATMENT. EVEN IF THE DRUG IS SUPER-EFFICIENT, IF IT STILL CAUSES OFF-TARGET TOXICITY AND DAMAGES NON-CANCEROUS CELLS AND TISSUES, THE DRUG WOULDN’T BE A GREAT REMEDY TO TREAT THAT PARTICULAR DISEASE. AS SUCH, THE GREATER POTENTIAL OF USING DOXORUBICIN AS ANTICANCER THERAPEUTIC DEPENDS ON THE AVAILABILITY OF A TARGETED DELIVERY VEHICLE, WHICH WILL NOT ONLY ENHANCE THE KILLING OF CANCER CELLS BUT ALSO MINIMIZE THE OFF-TARGET TOXICITY TO NON-CANCEROUS CELLS. THE GOAL OF THIS STUDY IS TO ENHANCE THE DELIVERY OF DOXORUBICIN BY FORMULATING AN APTAMER-LABELED LIPOSOMAL NANOPARTICLE DELIVERY SYSTEM THAT WILL CARRY AND DELIVER DOXORUBICIN SPECIFICALLY INTO CHEMORESISTANT HER-2+ BREAST CANCER CELLS. WE HAVE RECENTLY REPORTED THAT DOWN REGULATING NUCLEAR EXPRESSION OF MDR1 P-GP (ABCB1 GENE) BY P-GP SPECIFIC SIRNA COULD INCREASE THE DELIVERY OF DOXORUBICIN TO DOXORUBICIN RESISTANT BREAST CANCER CELLS. HOWEVER, SINCE THE DOX WAS DELIVERED AS A FREE DRUG SOLUTION WITHOUT ENCAPSULATING IT INTO A PARTICLE FOR TARGETED DELIVERY, IT STILL CAUSED TOXICITY TO OTHER NON-CANCEROUS CELLS. THE TARGETED DELIVERY OF SIRNA TO KNOCKDOWN MULTI-DRUG RESISTANT GENES SUCH AS MDR1 P-GP, MRP OR BCRP MIGHT BE HELPFUL TO CIRCUMVENT MDR USING THE APT-LABELED FORMULATIONS THAT WE HAVE DEVELOPED IN OUR LAB, HOWEVER, THERE ARE SOME QUESTIONS THAT STILL NEED TO BE ADDRESSED (1) HOW CAN WE DELIVER DOXORUBICIN IN A MORE TARGETED FASHION TO THE CHEMORESISTANT BREAST CANCER CELLS SO THAT THE DRUG-ENHANCED CYTOTOXICITY TO CANCER CELLS INCREASES WITH A MINIMAL TOXICITY TO THE NON-CANCEROUS CELLS? WE ASSUME THAT A TARGETED DELIVERY SYSTEM IS AN UTMOST REQUIREMENT WHETHER IT IS DELIVERING SIRNA TO SILENCE CHEMORESISTANT GENES OR AN ACTUAL CHEMODRUG WHICH WILL KILL CANCER CELLS WITHOUT KILLING NON- CANCEROUS CELLS. TO ADDRESS THE CHEMORESISTANCE AS WELL AS OFF-TARGET TOXICITY, A TARGETED DELIVERY SYSTEM FOR DOXORUBICIN NEEDS TO BE DEVELOPED WHICH SHOULD BE INNOVATIVE, COMPARABLE AND CAN MINIMIZE THE TOXICITY TO OTHER NON-CANCEROUS CELLS. AND (2) A STRATEGY NEEDS TO BE IN PLACE TO DETERMINE WHETHER THE TARGETED NANOPARTICLES WILL CARRY BOTH DOXORUBICIN AND SIRNA WITHIN THE SAME PARTICLES OR IN DIFFERENT PARTICLES TO GET THE BEST RESULTS PREVENTING CHEMORESISTANCE AND LIMITING OFF- TARGET TOXICITY. OUR HYPOTHESIS IS THAT DELIVERING DOXORUBICIN AND MDR-SILENCING SIRNAS SEPARATELY BY TARGETED NANOPARTICLE SYSTEM WILL ENHANCE THE CELLULAR TOXICITY AND ANTITUMOR EFFECTS AS COMPARED TO A TARGETED NANOPARTICLE SYSTEM THAT DELIVERS THE DRUG AND SIRNA SIMULTANEOUSLY. THIS HYPOTHESIS WILL BE TESTED THROUGH TWO SPECIFIC AIMS: AIM 1: TARGETED DELIVERY OF DOXORUBICIN LIPOSOMES FOR HER-2 POSITIVE BREAST CANCER TREATMENT. AIM 2: ASSESS WHETHER THE TARGETED NANOPARTICLES WILL CARRY BOTH DOXORUBICIN AND SIRNA WITHIN THE SAME PARTICLES OR IN DIFFERENT PARTICLES TO GET THE BEST RESULTS PREVENTING CHEMORESISTANCE AND LIMITING OFF-TARGET TOXICITY.

COLLABORATIVE RESEARCH: RESEARCH INFRASTRUCTURE: EPIIC: PRISTINE PARTNERSHIPS TO PROMOTE RESEARCH & INNOVATION FOR SOCIETAL IMPACT & NOVEL ENGAGEMENTS -PRISTINE (PARTNERSHIPS TO PROMOTE RESEARCH & INNOVATION FOR SOCIETAL IMPACT & NOVEL ENGAGEMENTS) IS A COLLABORATION AMONG THREE PRIMARILY UNDERGRADUATE INSTITUTIONS (PUI) THAT ARE COMMITTED TO DEVELOPING ACADEMIC-INDUSTRY PARTNERSHIPS TO ENHANCE INNOVATION AND PROMOTE WORKFORCE DEVELOPMENT THROUGHOUT THEIR REGIONS. THE COMPOSITION OF THE PRISTINE COHORT ? PRIVATE AND PUBLIC UNIVERSITIES, LIBERAL ARTS AND COMMUNITY COLLEGES, URBAN AND RURAL COMMUNITIES ? POSITIONS THE COHORT WELL TO ENGAGE AND ADVANCE THE ECONOMIC VIABILITY OF SMALL AND MEDIUM SIZED BUSINESSES NOT TYPICALLY ABLE TO CONTRIBUTE TO USE-INSPIRED RESEARCH (UIR) AND/OR INNOVATIONS MADE POSSIBLE BY EMERGING TECHNOLOGIES. UIR IS AIMED AT SOLVING REAL-WORLD PROBLEMS, LEADING TO FASTER AND MORE EFFECTIVE SOLUTIONS THAN ANY ONE ORGANIZATION COULD DEVELOP ON ITS OWN. THE EFFORT WILL ESTABLISH A COMMUNITY OF PRACTICE THAT IS DESIGNED TO BUILD CAPACITY, ESPECIALLY AT SMALLER INSTITUTIONS OF HIGHER EDUCATION AND PUIS, TO DEVELOP, IMPLEMENT, AND STRENGTHEN EXTERNAL RESEARCH INNOVATION PARTNERSHIPS IN EMERGING TECHNOLOGIES. PRISTINE WILL ENHANCE THE COHORT?S INDIVIDUAL AND COLLECTIVE CAPACITIES TO: CULTIVATE EXTERNAL PARTNERSHIPS THAT WILL ATTRACT RESEARCH FUNDING AND FACILITATE UIR IN EMERGING TECHNOLOGY FIELDS; LEVERAGE OUR EXPERTISE IN EXPERIENTIAL LEARNING TO DEVELOP CREDENTIALED WORKFORCE TRAINING PROGRAMS; AND SUPPORT FACULTY AND STAFF TO DEEPEN THEIR EXPERTISE AROUND GRANT SEEKING AND TECHNOLOGY TRANSFER TO INCREASE THE NUMBER OF FORMAL PROPOSALS AND AGREEMENTS BETWEEN INSTITUTIONS AND INDUSTRY PARTNERS. THE COHORT INTENDS TO DEVELOP RESOURCES AND TRAINING IN THESE AREAS FOR FACULTY AND INDUSTRY PARTNERS, AND DISSEMINATE THEIR LEARNINGS THROUGH A PUBLIC-FACING VIRTUAL PLAYBOOK/WEBSITE. 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.

EXAMINING THE ROLE OF ALLOSTATIC LOAD AND NEIGHBORHOOD DISADVANTAGE IN COGNITIVE FUNCTION TRAJECTORIES AMONG MIDLIFE AND OLDER BLACK AMERICANS - PROJECT SUMMARY BLACK AMERICANS ARE TWICE AS LIKELY TO DEVELOP ALZHEIMER’S DISEASE (AD) THAN WHITE AMERICANS. THE BIOPSYCHOSOCIAL DETERMINANTS OF COGNITIVE FUNCTION, AN EARLY-STAGE COMPONENT OF THE AD CONTINUUM, ARE LESS UNDERSTOOD IN THE BLACK POPULATION. ALLOSTATIC LOAD (AL), AN INDICATOR OF MULTISYSTEM (E.G., NERVOUS, CARDIOVASCULAR) PHYSIOLOGICAL DYSREGULATION DRIVEN BY CHRONIC PSYCHOSOCIAL STRESS, MAY BE ONE DETERMINANT OF POOR COGNITIVE FUNCTION. THE NEIGHBORHOOD IS AN EMERGING SOCIAL DETERMINANT OF COGNITIVE FUNCTION THAT MAY BE ESPECIALLY RELEVANT FOR BLACK AMERICANS GIVEN HISTORICAL SYSTEMS OF SOCIOECONOMIC AND RESIDENTIAL DISADVANTAGE. NEIGHBORHOOD DISADVANTAGE TOGETHER WITH PERCEIVED NEIGHBORHOOD STRESSORS MAY EXACERBATE AL, TO THE DETRIMENT OF COGNITIVE FUNCTION FOR MIDLIFE AND OLDER BLACK ADULTS. THE OVERALL RESEARCH OBJECTIVE IS TO EXAMINE THE RELATIONSHIP BETWEEN AL AND COGNITIVE FUNCTION AND WHETHER THIS ASSOCIATION IS IMPACTED BY BOTH NEIGHBORHOOD DISADVANTAGE [I.E., NEIGHBORHOOD SOCIOECONOMIC STATUS (SES) AND BLACK-WHITE SEGREGATION] AND PERCEIVED NEIGHBORHOOD STRESSORS (I.E., HIGH DISORDER AND LOW SOCIAL COHESION) WITHIN BLACK MIDLIFE AND OLDER ADULTS. SECONDARY, LONGITUDINAL DATA WILL COME FROM THE 2006-2016 WAVES OF THE HEALTH AND RETIREMENT STUDY, A NATIONALLY REPRESENTATIVE STUDY OF HEALTH AMONG THE MIDLIFE AND OLDER (>50 YEARS OF AGE) US ADULT POPULATION. SPECIFIC AIMS FOR THIS PROJECT INCLUDE: (AIM 1) TESTING THE RELATIONSHIP BETWEEN AL AND COGNITIVE FUNCTION USING BASELINE LINEAR REGRESSION AND GROWTH CURVE MODELS; (AIM 2) EXAMINING THE MODERATING ROLES OF NEIGHBORHOOD SES AND BLACK-WHITE SEGREGATION ON THE RELATIONSHIP BETWEEN AL AND COGNITIVE FUNCTION TO PREDICT BASELINE COGNITIVE FUNCTION AND CHANGE OVER TIME USING CROSS-SECTIONAL LINEAR REGRESSION MODELS AND GROWTH CURVE MODELS; AND (AIM 3) ANALYZING THE ASSOCIATION BETWEEN AL, PERCEIVED NEIGHBORHOOD STRESSORS, AND COGNITIVE FUNCTION IN BASELINE LINEAR MODELS AND GROWTH CURVE MODELS STRATIFIED BY LEVELS OF (1) NEIGHBORHOOD SES AND (2) BLACK-WHITE SEGREGATION. THE POSITIVE IMPACT OF THE PROPOSED RESEARCH WILL BE AN INCREASED UNDERSTANDING OF COMPLEX, MULTIFACTORIAL SOCIAL-ENVIRONMENTAL AND BIOLOGICAL DETERMINANTS OF COGNITIVE FUNCTION AMONG BLACK AMERICANS. FURTHERMORE, BY MENTORING UNDERREPRESENTED STUDENTS AT XAVIER UNIVERSITY OF LOUISIANA I WILL CONTRIBUTE TO INCREASING DIVERSITY IN THE AGING RESEARCH PIPELINE AND EXPANDING MY UNIVERSITY’S POPULATION HEALTH AND AGING RESEARCH CAPACITY.

EXCELLENCE IN RESEARCH: MICRORNA DETECTION STRATEGIES VIA EXPLORATION OF FLAVIN BINDING ALLOSTERIC SWITCHES

TARGETED DEGRADATION OF HIV INTEGRASE AS A NOVEL TREATMENT OF INFECTION - TARGETED DEGRADATION OF HIV INTEGRASE AS A NOVEL TREATMENT OF INFECTION PROJECT SUMMARY DUE TO THE DEVELOPMENT OF ANTIRETROVIRAL THERAPY, HIV-1 INFECTION IS NO LONGER A DEATH SENTENCE BUT RATHER A TREATABLE CHRONIC DISEASE, PROVIDING PEOPLE WITH HIV AN ALMOST NORMAL LIFE EXPECTANCY. HOWEVER, THE MOST RECENT WHO HIV DRUG RESISTANCE REPORT INDICATES THAT THE PREVALENCE OF ACQUIRED AND TRANSMITTED HIV DRUG RESISTANCE HAS EXPONENTIALLY INCREASED IN THE RECENT YEARS. THE PREVALENCE OF THREE AND FOUR-CLASS RESISTANT HIV IS ALREADY ESTIMATED TO RANGE FROM 5 TO 10% IN EUROPE, WHILE SOMEWHAT LOWER RATES ARE STILL REPORTED FOR NORTH AMERICA (<3%). INDEED, PAN-RESISTANT VIRUSES AGAINST SOME DRUG CLASSES HAVE ALREADY BEEN REPORTED. IT SEEMS INEVITABLE THAT FULLY DRUG RESISTANT VIRUSES WILL ARISE IN THE NOT-TOO-DISTANT FUTURE, WHICH NECESSITATES THE DEVELOPMENT OF NOVEL ANTI-HIV DRUGS. RATHER THAN CONTINUE TO DESIGN NEW INHIBITORS FOR DRUG-RESISTANT HIV, WE PROPOSE AN ALTERNATIVE STRATEGY – THE DEVELOPMENT OF PROTEOLYSIS-TARGETING CHIMERAS (PROTACS) USING EXISTING ANTI-HIV DRUGS. PROTACS ARE SMALL, BIFUNCTIONAL MOLECULES THAT CONTAIN A WARHEAD DOMAIN SPECIFIC TO THE TARGETED PROTEIN OF INTEREST COUPLED BY A SHORT LINKER TO AN E3 UBIQUITIN LIGASE BINDING DOMAIN. RATHER THAN WORKING AS A CLASSICAL INHIBITOR, THESE SMALL MOLECULES PROMOTE UBIQUITINATION AND SUBSEQUENT PROTEASOMAL DEGRADATION OF THE TARGET PROTEIN. USING THIS TECHNIQUE TO DEGRADE PATHOLOGICAL PROTEINS HAS THE ADDED BENEFIT THAT PROTACS CAN OFTEN BE USED AT CONCENTRATIONS SIGNIFICANTLY LOWER THAN STANDARD INHIBITORS, AS THERE IS NO NEED FOR PROTACS TO BE PRESENT AT STOICHIOMETRIC CONCENTRATIONS. ONCE A PROTAC INDUCES UBIQUITINATION OF THE TARGET PROTEIN, THE PROTEIN IS DEGRADED AND THE PROTAC IS FREE TO BIND ANOTHER PROTEIN AND REPEAT THE CYCLE. OF PARTICULAR IMPORTANCE TO THIS PROJECT IS THAT THE TRANSIENT NATURE OF PROTAC INTERACTION WITH, AND SUBSEQUENT UBIQUITINATION OF THE TARGET PROTEIN MEANS THAT A HIGH AFFINITY DRUG-TARGET INTERACTION IS NOT AS NECESSARY AS WITH CLASSICAL STOICHIOMETRIC INHIBITORS. INDEED, PROTACS DEVELOPED FOR ONCOGENIC KINASES USING EXISTING INHIBITORS AS THE WARHEAD DOMAIN WERE ABLE TO INDUCE DEGRADATION OF KINASES WITH MUTATIONS THAT CONFERRED RESISTANCE TO THE SAME INHIBITORS. WE POSTULATE THAT IT WILL BE POSSIBLE TO TARGET HIV PROTEINS IN VIRUS THAT HAS BECOME RESISTANT TO THE INHIBITORY EFFECT OF A DRUG WITH THE CORRESPONDING PROTAC, DUE TO THE LOWER BINDING AFFINITY REQUIRED FOR DEGRADATION COMPARED TO INHIBITION. OUR EARLY STAGE PROTACS DESIGNED TO INDUCE DEGRADATION OF THE HIV INTEGRASE ENZYME SHOW NANOMOLAR EFFICACY IN BOTH PROTEOLYSIS OF INTEGRASE, AS WELL AS A BLOCKADE OF DE NOVO HIV INFECTION IN T CELLS USING WELL-ESTABLISHED ASSAYS. THIS APPLICATION COMBINES THE EXPERTISE OF INVESTIGATORS IN PROTAC DESIGN AND BIOLOGICAL ASSAY DEVELOPMENT WITH THAT OF AN ESTABLISHED RESEARCH TEAM AT AN NIH CFAR SITE. OUR GOAL IS THE DEVELOPMENT OF PROOF-OF-PRINCIPLE PROTACS THAT TEST THE HYPOTHESIS THAT PROTACS ARE ACTIVE AGAINST VIRUSES THAT HAVE DEVELOPED RESISTANCE MUTATIONS IN THE VIRAL PROTEIN THAT IS TARGETED BY THE PROTAC WARHEAD. AS EXPECTED FOR AN R21 APPLICATION, THIS IS A HIGH-RISK PROPOSAL; BUT IF SUCCESSFUL, THE OUTCOME WILL PROVIDE NEW AVENUES FOR ANTI-HIV DRUG DEVELOPMENT FOR THE INCREASINGLY RESISTANT HIV VIRUS.

EXCELLENCE IN RESEARCH: A COMPUTATIONAL STUDY OF THE GAS-PHASE REACTIONS OF SIMPLE EPOXIDES AND THEIR RADICALS -WITH THIS AWARD, THE CHEMICAL STRUCTURE, DYNAMICS, AND MECHANISMS-B PROGRAM IS SUPPORTING PROFESSOR KATHLEEN MORGAN AND HER STUDENTS AT XAVIER UNIVERSITY OF LOUISIANA TO STUDY THE CHEMISTRY OF EPOXIDES, A TYPE OF VOLATILE ORGANIC COMPOUND WHICH IS COMMONLY FOUND IN THE ATMOSPHERE. INCREASINGLY, CITIZENS ARE RECOGNIZING THE POTENTIAL DANGERS OF INDUSTRIAL PLANTS THAT PRODUCE AND STORE HAZARDOUS CHEMICALS, AND ONE MAJOR CONCERN IS THE RELEASE OF VOLATILE ORGANIC COMPOUNDS (VOC) INTO THE AIR THEY BREATHE. THIS STUDY IS CONCERNED WITH THE 'EPOXIDE' CLASS OF COMPOUNDS. ETHYLENE OXIDE AND PROPENE OXIDE ARE COMMON COMMODITY CHEMICALS OF THE EPOXIDE FAMILY WITH A VARIETY OF IMPORTANT COMMERCIAL PURPOSES BUT THEY ARE ALSO CARCINOGENIC. UNDERSTANDING THE FATE OF THESE AND RELATED VOC IN THE ATMOSPHERE, THROUGH KNOWLEDGE OF LIKELY DECOMPOSITION MECHANISMS AND RATES, IS CRITICAL. THE PROPOSED COMPUTATIONAL MODELING STUDY SEEKS TO EXTEND OUR UNDERSTANDING OF THE DEGRADATION REACTIONS, AND HAS THE POTENTIAL TO SUGGEST NEW REACTIONS THAT CAN REMEDIATE POLLUTANTS. THE STUDY IS DESIGNED FOR FULL PARTICIPATION BY UNDERGRADUATE RESEARCH STUDENTS FROM XAVIER UNIVERSITY OF LOUISIANA, A PRIMARILY UNDERGRADUATE AND HISTORICALLY BLACK COLLEGE OR UNIVERSITY (HBCU), WHERE THE MAJORITY OF STUDENTS ARE AFRICAN AMERICAN WOMEN, AND SCIENCE MAJORS. THE COMPUTATIONAL ANALYSES PROVIDE EXCELLENT TRAINING EXPERIENCES FOR UNDERGRADUATES THAT WILL PREPARE THEM FOR GRADUATE STUDIES AND CAREERS IN STEM (SCIENCE, TECHNOLOGY, ENGINEERING AND MATHEMATICS) FIELDS. THIS STUDY WILL ALSO ENABLE STUDENTS TO CONNECT BASIC SCIENCE RESEARCH TO THE REAL-WORLD PROBLEMS THAT UNDERLIE THIS PROJECT. THE PROPOSED COMPUTATIONAL STUDY IS CONCERNED WITH GAS-PHASE RADICAL REACTIONS OF SIMPLE EPOXIDES. EPOXIDES OF INTEREST INCLUDE ETHYLENE OXIDE, PROPENE OXIDE, CIS- AND TRANS-2-BUTENE OXIDE, 2-METHYLPROPENE OXIDE, AND EPIFLUOROHYDRIN. THREE TYPES OF CALCULATIONS, USING COMMERCIALLY-AVAILABLE SOFTWARE, WILL BE CONSIDERED TO EXPLORE THE INFLUENCE OF SUBSTITUENTS ON EPOXIDE REACTIVITY: (1) EPOXIDE BOND DISSOCIATION ENERGIES; (2) DEGRADATION OF PARENT EPOXIDES AND/OR THEIR RADICAL COUNTERPARTS; AND (3) ADDITION REACTIONS OF HYDROXYL RADICAL AND OTHER RADICAL SPECIES TO EPOXIDES. TOGETHER, THESE CALCULATIONS WILL PROVIDE INSIGHT INTO THE BEHAVIOR OF EPOXIDES IN THE GAS PHASE, AND THE EFFECTS OF SUBSTITUENTS ON EPOXIDE REACTIVITY AND DECOMPOSITION PRODUCTS. THROUGH THIS PROJECT, THE DETAILED TRAINING PROGRAM FOR UNDERGRADUATE MINORITY STUDENTS IS EXPECTED TO MAKE AN IMPORTANT CONTRIBUTION TO THE DEVELOPMENT OF A DIVERSE WORKFORCE FOR THE NATION. 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.

LEAPS-MPS: GEOMETRIC AND QUANTITATIVE ANALYSIS OF NONLINEAR PDES -THE THEORETICAL AND NUMERICAL ANALYSIS OF NONLINEAR PARTIAL DIFFERENTIAL EQUATIONS (PDES) PLAY SIGNIFICANT ROLES IN A VARIETY OF APPLICATIONS. HOWEVER, AN IMMEDIATE CHALLENGE LIES IN ASCERTAINING THE COMPUTATIONAL ACCURACY OF NUMERICAL SCHEMES REQUIRED FOR SOLVING SUCH PDES, WHEN THEIR SOLUTIONS LACK SUFFICIENT REGULARITY. THIS RESEARCH PROJECT POSES A SERIES OF FUNDAMENTAL QUESTIONS TOGETHER WITH STEPS FOR THEIR RESOLUTION, AIMED AT ADVANCING AND DEVELOPING THE REGULARITY THEORY FOR SYSTEMS OF HYPERBOLIC CONSERVATION LAWS, USING TOOLS FROM ANALYSIS AND GEOMETRIC MEASURE THEORY. THE OBTAINED OUTCOMES WILL PROPEL THIS FIELD OF RESEARCH TOWARDS MORE EXCITING OPEN QUESTIONS AND YIELD INCREASINGLY ACCURATE NUMERICAL SCHEMES OF PRACTICAL VALUE FOR THESE EQUATIONS. FURTHERMORE, THIS PROJECT EMPHASIZES SEVERAL PROSPECTS, SUCH AS RESEARCH EXPOSURE, SPECIALIZED MENTORING PROGRAMS AND OUTREACH EVENTS, TO CREATE A TRAINING GROUND IN MATHEMATICAL EDUCATION AND RESEARCH FOR UNDERGRADUATE STUDENTS AT XAVIER UNIVERSITY OF LOUISIANA AND BEYOND. THERE ARE TWO MAIN PARTS TO THIS RESEARCH PROJECT. THE FIRST PART IS DIRECTED TOWARDS PROVIDING A GEOMETRIC DESCRIPTION FOR SYSTEMS OF CONSERVATION LAWS AND EXPLORING THE REGULARITY OF THEIR SOLUTIONS USING APPROXIMATION THEORY. REFORMULATING SYSTEMS OF HYPERBOLIC CONSERVATION LAWS IN A LAGRANGIAN FORM PROVIDES AN EQUIVALENT REPRESENTATION OF SYSTEMS BY MEANS OF PARTICLE PATHS. THIS SEGMENT WILL FOCUS ON STUDYING THE RELATION BETWEEN LAGRANGIAN AND EULERIAN FORMULATIONS OF CONSERVATION LAWS, RENEWING INTEREST IN THIS TOPIC FROM A GEOMETRIC POINT OF VIEW. HERE, THE GOALS ARE TO: (I) DESCRIBE SYSTEMS OF CONSERVATION LAWS USING THE NOTION OF PARTICLE PATHS THAT ARE IN THE FORM OF WEAK DIFFEOMORPHISMS AND ESTABLISH THESE AS EXTREMALS OF AN ACTION FUNCTIONAL DEFINED ON THE CORRESPONDING ALGEBRA IN THE EULERIAN FORMULATION; AND (II) MEASURE THE REGULARITY OF SOLUTIONS TO SYSTEMS OF CONSERVATION LAWS, PARTICULARLY FOR TEMPLE SYSTEMS, USING APPROXIMATION SPACES CHARACTERIZED IN TERMS OF BESOV SPACES. THE SECOND PART OF THE PROJECT WILL FOCUS ON PERFORMING A QUANTITATIVE ANALYSIS OF THE TWO-COMPONENT FORNBERG-WHITHAM (FW) SYSTEM IN BESOV SPACES TO INVESTIGATE THE POSSIBILITY OF A GLOBAL IN TIME SOLUTION AND CRITERIA FOR WAVE-BREAKING. THE TWO-COMPONENT FW SYSTEM IS A MODEL FOR STUDYING SURFACE WAVES IN SHALLOW WATER. ESTABLISHING ITS WELL-POSEDNESS AND ANALYZING CONDITIONS FOR GLOBAL EXISTENCE OF ITS STRONG SOLUTIONS ARE CHALLENGING PROBLEMS ASSOCIATED WITH THIS SYSTEM IN VARIOUS FUNCTION SPACES. AS PART OF THIS PROJECT, THE FW SYSTEM WILL BE EXAMINED IN BESOV SPACES, WHICH ARE FUNCTION SPACES RECEIVING INCREASING ATTENTION IN THE RECENT YEARS AS THEY GENERALIZE SOBOLEV SPACES AND ARE MORE EFFECTIVE AT MEASURING REGULARITY OF FUNCTIONS. THIS EXERCISE IS AIMED AT BREAKING NEW GROUND BY (I) DEVELOPING A QUANTITATIVE ANALYSIS OF GLOBAL STRONG SOLUTIONS AND SEEKING GLOBAL WEAK SOLUTIONS FOR THE FW SYSTEM IN BESOV SPACES; AND (II) INVESTIGATING WAVE BREAKING FOR THE FW SYSTEM CORRESPONDING TO A LARGE CLASS OF INITIAL DATA, WHILE ADAPTING METHODS USED TO EXAMINE THE FORNBERG-WHITHAM EQUATION THAT REMAINS RELEVANT IN SEVERAL AREAS OF RESEARCH IN PHYSICS AND IS MORE RECENTLY BEING STUDIED IN COASTAL OCEANOGRAPHY. 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.

ORE-CZ: METHANE EMISSION FROM WETLANDS SURROUNDING LAKE PONTCHARTRAIN -WETLANDS EMIT METHANE, A POTENT GREENHOUSE GAS. THE CHARACTERISTICS OF THIS EMISSION DEPEND ON THE INDIVIDUAL CHARACTERISTICS OF THE WETLAND. IN THIS RESEARCH, THE FOCUS IS ON THE WETLANDS OF LAKE PONTCHARTRAIN, WHICH IS ONE OF THE LARGEST WETLANDS ALONG THE GULF COAST OF NORTH AMERICA. THESE WETLANDS ARE UNDER CONSIDERABLE STRESS DUE TO EROSION, CONSTRUCTION OF LEVEES AND CANALS, SALTWATER INTRUSION FROM THE GULF OF MEXICO, AND URBANIZATION. AGAINST THIS BACKDROP, THE SPECIFIC RESEARCH PLAN IS TO ASSESS METHANE EMISSIONS FROM THE SOIL AT DIFFERENT LOCATIONS ALONG LAKE PONTCHARTRAIN USING INFRARED SPECTROSCOPY AND COMPARE THE DATA TO THOSE REPORTED IN THE LITERATURE FOR OTHER WETLANDS. THE RESEARCH WILL ALSO STUDY THE RELATION OF THE SOIL CHARACTERISTICS AND THE LOCAL ENVIRONMENT WITH THE OBSERVED EMISSION PATTERN OF THE GAS. THE OUTCOME OF THIS WORK CAN SHOW HOW THE LARGE WETLANDS AROUND LAKE PONTCHARTRAIN CONTRIBUTE TO GLOBAL METHANE EMISSIONS AND THE FACTORS THAT DRIVE THE RELEASE OF THE GAS FROM THE INVESTIGATED WETLANDS. FURTHERMORE, THE FINDINGS WILL PROVIDE INFORMATION THAT CAN ENABLE BETTER MANAGEMENT OF WETLANDS AND SUPPORT LOUISIANA?S EFFORT TOWARD NET-ZERO GREENHOUSE GAS EMISSIONS BY 2050, WHICH INCLUDES A PLAN TO USE RESTORED WETLANDS AS A SINK FOR LONG-TERM CARBON STORAGE. THIS PROJECT PROVIDES RESEARCH OPPORTUNITIES IN STEM FOR UNDERGRADUATE STUDENTS ENROLLED AT A HISTORICALLY BLACK COLLEGE AND UNIVERSITY, AND IT IS SUPPORTED IN PART BY THE HBCU-UNDERGRADUATE PROGRAM AT THE NATIONAL SCIENCE FOUNDATION. WETLANDS CONTRIBUTE ABOUT 30% OF GLOBAL METHANE EMISSIONS AND ARE THUS A SIGNIFICANT CONTRIBUTOR TO THE ACCUMULATION OF THIS GREENHOUSE GAS IN THE ATMOSPHERE. DESPITE MANY RESEARCH REPORTS, DISCREPANCIES BETWEEN THEORETICAL AND MEASURED METHANE ESTIMATION AND PATTERNS FROM INDIVIDUAL WETLANDS ARE OBSERVED. INCONSISTENCIES ARISE BECAUSE METHANE EMISSION FROM A PARTICULAR WETLAND IS DEPENDENT ON WATER LEVEL, SOIL CHARACTERISTICS, VEGETATION TYPE, AND TOPOGRAPHY. THIS RESEARCH FOCUSES ON ASSESSING METHANE GAS FROM WETLANDS AROUND LAKE PONTCHARTRAIN, ONE OF THE LARGEST ALONG THE GULF COAST OF NORTH AMERICA, WHICH HAS SEEN A STEADY LOSS OF WETLAND AREA AND A GRADUAL CONVERSION OF FRESHWATER TO SALTWATER VEGETATION TYPES. A UNIQUE STRESSOR TO THE WETLANDS IS THE URBAN SPRAWL OF NEW ORLEANS AND ITS SUBURBS, WHOSE EFFLUENTS IMPACTS THE WETLANDS. THE PLAN IS TO USE PORTABLE, USER-FRIENDLY INFRARED-BASED DEVICES TO COLLECT SOIL METHANE EMISSIONS UNDER DIFFERENT CONDITIONS FROM VARIOUS WETLAND LOCATIONS SURROUNDING LAKE PONTCHARTRAIN AND INTEGRATE THE FINDINGS INTO THE LARGER FRAMEWORK OF CARBON CYCLING FROM WETLANDS. TO THIS END, THE RESEARCH WILL MODIFY EXISTING METHANE COLLECTION PROTOCOLS, TEST SOIL CHARACTERISTICS, SURVEY HEAVY METAL CONTAMINATION AND ASSESS THE BIOLOGICAL ACTIVITY OF THE WETLAND SOIL. THE OBJECTIVE IS TO UNDERSTAND THE RELATION BETWEEN STRESSORS AND THE EMISSION PATTERN OF THE GAS FROM THE WETLANDS. THE RESULT IS EXPECTED TO LEAD TO BETTER MANAGEMENT OF WETLANDS AND SUPPORT LOUISIANA?S PLAN TO OPTIMIZE THE CARBON SEQUESTRATION POTENTIAL THROUGH WETLAND RESTORATION EFFORTS. 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.

ACTIVATED FOODS PROMOTE HEALTH

EMB: COLLABORATIVE RESEARCH: USING MATHEMATICS TO BRIDGE BETWEEN EVOLUTIONARY DYNAMICS IN THE HEMATOPOIETIC SYSTEMS OF MICE AND HUMANS: FROM IN VIVO TO EPIDEMIOLOGICAL SCALES -THIS PROJECT IS A COLLABORATION BETWEEN THREE INSTITUTIONS: UNIVERSITY OF CALIFORNIA-SAN DIEGO, XAVIER UNIVERSITY OF LOUISIANA, AND UNIVERSITY OF CALIFORNIA-IRVINE. THE HUMAN BLOOD CONTAINS DIFFERENT CELL TYPES THAT ARE CONTINUOUSLY PRODUCED, WHILE OLDER CELLS DIE. AS THIS PROCESS CONTINUES WHILE THE ORGANISM AGES, MISTAKES ARE MADE DURING CELL PRODUCTION, GENERATING MUTANT CELLS. THESE MUTANTS CAN LINGER IN THE BLOOD AND BECOME MORE ABUNDANT OVER TIME. THEY CAN CONTRIBUTE TO CHRONIC HEALTH CONDITIONS AND THERE IS A CHANCE THAT THEY INITIATE CANCER. IT IS NOT WELL UNDERSTOOD WHY THESE MUTANT CELLS PERSIST AND EXPAND. ONE PROBLEM THAT HAS HELD BACK PROGRESS IS THAT FOR OBVIOUS REASONS IT IS IMPOSSIBLE TO PERFORM EXPERIMENTS WITH HUMAN SUBJECTS TO INVESTIGATE THIS. MATHEMATICS COMBINED WITH EPIDEMIOLOGICAL DATA, HOWEVER, OFFERS A WAY AROUND THIS LIMITATION. THIS PROJECT DEVELOPS MATHEMATICAL MODELS DESCRIBING THE EVOLUTION OF MUTANT CELLS IN THE BLOOD OVER TIME, USING EXPERIMENTAL MOUSE DATA TO DEFINE THE MODEL STRUCTURE. NEW MATHEMATICAL APPROACHES ARE THEN USED TO ADAPT THIS MODEL TO THE HUMAN BLOOD SYSTEM, BY BRIDGING BETWEEN MATHEMATICAL MODELS OF MUTANT EVOLUTION IN THE BLOOD, AND THE EPIDEMIOLOGICAL AGE-INCIDENCE OF MUTANTS IN THE HUMAN POPULATION. THERE IS BROAD PUBLIC HEALTH IMPACT, SINCE THIS WORK CAN SUGGEST WAYS TO REDUCE THE MUTANT CELLS IN PATIENTS, WHICH CAN ALLEVIATE CHRONIC HEALTH CONDITIONS AND REDUCE CANCER RISK. FROM THE EDUCATIONAL PERSPECTIVE, THE PIS COLLABORATE WITH XAVIER UNIVERSITY OF LOUISIANA, AN UNDERGRADUATE HISTORICALLY BLACK UNIVERSITY, TO FOSTER ENTHUSIASM IN CONTINUED EDUCATION AND CAREERS IN STEM, AND EQUIP STUDENTS WITH KNOWLEDGE AND SKILLS TO POTENTIALLY CONTINUE IN GRADUATE PROGRAMS AT TOP UNIVERSITIES, THUS PROMOTING SOCIAL MOBILITY. AS HIGHER ORGANISMS AGE, TISSUE CELLS ACQUIRE MUTATIONS THAT CAN RISE IN FREQUENCY OVER TIME. SUCH CLONAL EVOLUTIONARY PROCESSES HAVE BEEN DOCUMENTED IN MANY HUMAN TISSUES AND HAVE BECOME A MAJOR FOCUS FOR UNDERSTANDING THE BIOLOGY OF AGING. GAINING MORE INSIGHTS INTO MECHANISMS THAT DRIVE MUTANT EMERGENCE IN NON-MALIGNANT HUMAN TISSUES IS AN IMPORTANT BIOLOGICAL / PUBLIC HEALTH QUESTION THAT NEEDS TO BE ADDRESSED TO DEFINE CORRELATES OF TISSUE AGING. WHILE EXPERIMENTS IN MICE HAVE SUGGESTED POSSIBLE DRIVERS OF MUTANT EVOLUTION IN TISSUES, A CENTRAL UNRESOLVED QUESTION IS WHETHER (AND HOW) KNOWLEDGE FROM MURINE MODELS CAN BE APPLIED TO HUMANS. MATHEMATICS PROVIDES A NEW APPROACH TO ADDRESS THIS CHALLENGE: WE PROPOSE A MULTISCALE APPROACH THAT USES MATHEMATICS TO BRIDGE BETWEEN CELLULAR DYNAMICS OF MICE AND HUMANS, BY UTILIZING EPIDEMIOLOGICAL DATA OF MUTANT INCIDENCE IN HUMAN POPULATIONS. WE USE ?CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL? (CHIP) AS A STUDY SYSTEM, WHERE TET2 AND DNMT3A MUTANT CLONES EMERGE IN THE HISTOLOGICALLY NORMAL HEMATOPOIETIC SYSTEM. BASED ON STEM CELL TRANSPLANTATION EXPERIMENTS IN MICE, WE SEEK TO CONSTRUCT A PREDICTIVE MATHEMATICAL MODEL OF MUTANT EVOLUTION IN MICE. USING THE HAZARD FUNCTION, THIS IN VIVO MODEL CAN PREDICT THE EPIDEMIOLOGICAL INCIDENCE OF MUTANTS. FITTING PREDICTED TO OBSERVED MUTANT AGE-INCIDENCE DATA FOR HUMANS WILL YIELD A PARAMETERIZED AND PREDICTIVE MODEL OF HUMAN TET2 AND DNMT3A MUTANT EVOLUTION. PUBLIC HEALTH IMPACTS INCLUDE A BETTER UNDERSTANDING OF MUTANT EVOLUTION IN THE HUMAN HEMATOPOIETIC SYSTEM, WHICH MAY LEAD TO EVOLUTION-BASED INTERVENTION STRATEGIES TO REDUCE CHIP MUTANT BURDEN. 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.

IGF::OT::IGF CSPI SPRING 2015 TUITION OT CIERRA WILCOX XAVIER UNIVERSITY POC LISA HARRELL 504-520-6218 LHARRELL@XULA.EDU

IGF::OT::IGF FALL 2014: CSPI TUITION FOR OT WILCOX XAVIER UNIVERSITY OF LOUISIANA STUDENT ID # 900047815 POC: TRENICE PICKNERY SR STUDENT ACCOUNTS REPRESENTATIVE 504.520.5317-DIRECT 504.520.7667-MAIN

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XAVIER UNIVERSITY FALL CAREER FAIR 6 OCTOBER 2010 POC: MARIAN MINNARD 504-520-7909 COST: $3500

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