Kansas City University

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - NON-CONSTRUCTION

CA SIGNALING IN PROGRESSION OF AMYOTROPHIC LATERAL SCLEROSIS IN SKELETAL MUSCLE

PREDOCTORAL TRAINING IN GENERAL, PEDIATRIC, AND PUBLIC HEALTH DENTISTRY AND DENTAL HYGIENE

HEALTH AND PUBLIC SAFETY WORKFORCE RESILIENCY TRAINING PROGRAM

EDUCATION STABILIZATION FUND: HIGHER EDUCATION INSTITUTIONAL RELIEF AID

EDUCATION STABILIZATION FUND: HIGHER EDUCATION STUDENT RELIEF AID

YOUNG INFANTS' DETECTION OF EMOTION - PROJECT SUMMARY THE PERCEPTION OF EMOTION STARTS WITH EMOTION DETECTION, WHICH REFLECTS AN ABILITY TO DETERMINE WHETHER EMOTIONAL CONTENT IS PRESENT. THE DETECTION OF EMOTIONAL INFORMATION IS EVOLUTIONARILY RELEVANT, IN THAT IT ALLOWS FOR A RAPID BEHAVIORAL RESPONSE WHEN FACED WITH THREAT. EMOTION DETECTION (AND ITS RELATION TO IMMEDIATE THREAT) HAS PRIMARILY BEEN STUDIED WITH ADULTS AND VERY LITTLE IS KNOWN ABOUT THE DEVELOPMENT OF THIS CRITICAL ABILITY. THE K99 PORTION OF THIS PROPOSAL SEEKS TO REMEDY THE SITUATION BY TESTING INFANTS FOR DETECTION OF EMOTIONAL CONTENT IN VERY BRIEF STIMULUS PRESENTATIONS (50MS, 100MS, 200MS, 400MS). THE INFANTS WILL BE TESTED USING HAPPY, ANGRY, AND FEARFUL FACIAL EXPRESSIONS AND SACCADE LATENCIES TO DIFFERENT EMOTIONS WILL ESTABLISH WHETHER THEY ARE DIFFERENTIALLY DETECTED; SPECIFICALLY, IF THREAT-RELATED EMOTIONS (I.E., ANGER, FEAR) ARE DETECTED FASTER THAN NON- THREATENING EMOTION (HAPPINESS). ADDITIONALLY, EYE-TRACKING AND PUPILLOMETRY MEASURES WILL DETERMINE WHETHER INFANTS ARE UTILIZING SPECIFIC FEATURES TO DETECT DISTINCT EMOTIONS AND WHETHER PUPIL DIAMETER, AN INDEX OF AUTONOMIC NERVOUS SYSTEM (ANS) FUNCTION, IS ALTERED BY EMOTIONAL FACES. MOST IMPORTANTLY, THE R00 PHASE OF THIS AWARD WILL BE USED TO STUDY A LONGITUDINAL SAMPLE TO ASSESS INDIVIDUAL DIFFERENCES IN DETECTION SPEED ACROSS DEVELOPMENT AND DETERMINE WHETHER THESE RELATE TO LATER DEVELOPMENTAL ABILITIES. CANDIDATE: THE CANDIDATE HAS HER PH.D. IN EXPERIMENTAL PSYCHOLOGY AND HAS 2 YEARS OF POSTDOCTORAL RESEARCH EXPERIENCE. SHE HAS A STRONG PUBLICATION RECORD DESPITE A 4-YEAR ABSENCE FROM HER FIELD DUE TO HEALTH ISSUES. WITH THIS AWARD, SHE WILL REACH HER POTENTIAL TO BECOME A SUCCESSFUL INDEPENDENT INVESTIGATOR. TRAINING: SPECIFIC TRAINING IN THE ACQUISITION AND ANALYSES OF EYE-TRACKING DATA AND THE RELATED MEASURES OF PUPILLOMETRY WILL BE USEFUL IN HER PURSUIT OF A TENURE-TRACK POSITION AT A RESEARCH I/DOCTORATE EXTENSIVE UNIVERSITY. BECOMING COMFORTABLE USING MATLAB AND CONDUCTING ANALYSES USING ADVANCED STATISTICAL METHODS WILL BE APPROPRIATE TRAINING AIMS TO FACILITATE THIS GOAL. KU’S LIFE SPAN INSTITUTE IS AN INTERDISCIPLINARY RESEARCH CENTER FOCUSED ON DEVELOPMENT ACROSS THE LIFE SPAN, AND ITS COLLABORATIVE ENVIRONMENT WILL PROVIDE AN IDEAL SETTING FOR THE PROPOSED RESEARCH. RESEARCH: USING A CROSS-SECTIONAL STUDY WITH 3.5- AND 7.5-MONTH-OLD INFANTS, THE PROPOSED RESEARCH WILL DOCUMENT THE TIME COURSE OF EMOTION DETECTION, POTENTIAL PREFERENTIAL PROCESSING OF THREAT-RELATED EMOTIONS, HOW LOW-LEVEL VISUAL FEATURES INFLUENCE DETECTION, AND HOW ANS ACTIVITY IS DIFFERENTIALLY MODULATED BY EMOTIONAL CONTENT. THE R00 PHASE WILL ADD AN ADDITIONAL VISIT AT 12.5 MONTHS AND A FOLLOW-UP ASSESSMENT AT 18 MONTHS. THIS STUDY WILL ESTABLISH CROSS-AGE STABILITY ACROSS MEASURES AND EXAMINE THEIR PREDICTIVE VALIDITY FOR DEVELOPMENTAL OUTCOMES. DOCUMENTING THE DEVELOPMENT OF THIS VITAL SKILL IN EARLY INFANCY HAS POTENTIAL IMPLICATIONS IN THE STUDY OF TYPICAL AND ATYPICAL DEVELOPMENT, SUCH AS THAT IN AUTISM SPECTRUM DISORDER.

ENDOTHELIAL SMAD3 AS A NOVEL TARGET FOR ENHANCING ANGIOGENESIS IN THE FAILING HEART

INVESTIGATING THE ROLES OF PREGNANE X RECEPTOR IN HUMAN BREAST CANCERS - PROJECT SUMMARY/ABSTRACT BREAST CANCER IS THE SECOND MOST COMMON TYPE OF CANCER DIAGNOSED WORLDWIDE AND IS ALSO THE SECOND LEADING CAUSE OF CANCER-RELATED DEATHS AMONG WOMEN OVERALL. WHILE MUCH PROGRESS HAS BEEN MADE IN THE DIAGNOSIS AND TREATMENT OF BREAST CANCER, TRADITIONAL CHEMOTHERAPEUTIC TREATMENTS CAN LEAD TO THE DEVELOPMENT OF CHEMOTHERAPEUTIC RESISTANCE AND REMAINS A MAJOR CHALLENGE IN OVERALL PATIENT OUTCOMES. THE ACTIVATION OF THE PREGNANE X RECEPTOR (PXR) BY NUMEROUS ENDO- AND XENO-BIOTICS, INCLUDING SEVERAL CHEMOTHERAPEUTIC DRUGS, IS KNOWN TO REGULATE MANY OF THE METABOLIC PATHWAYS ASSOCIATED WITH DRUG METABOLISM AND RESISTANCE. THE LONG-TERM GOAL IS TO UNDERSTAND THE TRANSCRIPTIONAL AND METABOLIC TARGETS OF PXR IN HUMAN BREAST CANCERS, AND TO APPLY THIS KNOWLEDGE IN THEIR TREATMENT IN ORDER TO IMPROVE PATIENT OUTCOMES. THE OBJECTIVE OF THIS APPLICATION IS TO ELUCIDATE THE EFFECTS OF PXR EXPRESSION AND ACTIVATION ON THE TRANSCRIPTOME AND PHENOTYPIC CHANGES IN HUMAN BREAST CANCER CELL LINES. THE CENTRAL HYPOTHESIS, WHICH IS FORMULATED ON PXRS KNOWN ROLES IN DRUG METABOLISM IN HEALTHY AND PATHOGENIC TISSUES AS WELL AS PRELIMINARY DATA, IS THAT PXR ACTIVATION INCREASES XENOBIOTIC METABOLISM VIA THE INDUCTION OF PHASE I AND II ENZYMES, AS WELL AS PHASE III TRANSPORTERS, IN ADDITION TO ALTERATIONS IN THE CELL CYCLE AND APOPTOSIS IN BREAST CANCER. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT ONCE THE TRANSCRIPTIONAL AND PHENOTYPIC ALTERATIONS IN RESPONSE TO PXR ACTIVATION ARE IDENTIFIED, PHARMACOLOGICAL AGENTS OR REGIMES THAT INTERFERE WITH THESE PATHWAYS COULD BE DEVELOPED TO DECREASE THE CHEMORESISTANCE OF BREAST CANCER. THE OBJECTIVE OF THIS PROJECT WILL BE ACCOMPLISHED BY TWO SPECIFIC AIMS: (1) IDENTIFY GLOBAL GENE EXPRESSIONS CHANGES IN HUMAN BREAST CANCERS ASSOCIATED WITH PREGNANE X RECEPTOR EXPRESSION AND/OR TRANSCRIPTION FACTOR ACTIVATION. AN RNA-SEQ BASED APPROACH WILL BE USED TO IDENTIFY CHANGES TO THE TRANSCRIPTOME IN RESPONSE TO ENDOGENOUS AND EXOGENOUS PXR EXPRESSION AND ACTIVATION. (2) EXAMINE THE EFFECTS OF PXR EXPRESSION AND ACTIVATION IN MODELS OF BREAST CANCER ON CELL SURVIVAL AND CHEMORESISTANCE. IN- VITRO BASED ASSAYS EXAMINING THE EFFECTS OF PXR ON VARIOUS ASPECTS OF THE CELL CYCLE, SURVIVAL, APOPTOSIS, AND INVASIVENESS WILL BE UTILIZED. THIS STUDY IS INNOVATIVE BECAUSE IT SHIFTS THE FOCUS OF PXRS ROLES FROM NORMAL LIVER AND INTESTINAL DRUG METABOLISM IN ORDER TO FILL A LARGE VOID IN OUR UNDERSTANDING OF PXRS INFLUENCE ON BREAST CANCER, AND POTENTIALLY IN MANY OTHER TYPES OF CANCER AS WELL. THE PROPOSED PROJECT IS SIGNIFICANT BECAUSE IT WILL UNCOVER GENES AND METABOLIC PATHWAYS THAT ARE CRITICAL TO THE DEVELOPMENT OF CHEMOTHERAPEUTIC RESISTANCE IN BREAST CANCER, IDENTIFYING NEW POTENTIAL THERAPEUTIC TARGETS.

ENDOTHELIAL SMAD3 AS A NOVEL TARGET TO AVERT CHEMOTHERAPY INDUCED CARDIOMYOPATHY - PROJECT SUMMARY / ABSTRACT DUE TO ADVANCES IN EARLY DETECTION, IMPROVED THERAPIES AND SUPPORTIVE CARE, CANCER SURVIVAL RATES HAVE INCREASED SUBSTANTIALLY OVER THE PAST DECADES. THIS SUCCESS TRANSLATES INTO A RAPIDLY INCREASING NUMBER OF CANCER SURVIVORS WHO SUFFER FROM CARDIOVASCULAR COMPLICATIONS OF ANTICANCER THERAPY. OF PARTICULAR CONCERN ARE DOXORUBICIN AND OTHER ANTHRACYCLINE DRUGS THAT ARE USED TO TREAT HEMATOLOGICAL MALIGNANCIES, BREAST, OVARIAN, AND OTHER SOLID TUMORS. PATIENTS TREATED WITH THESE DRUGS SUFFER FROM LONG-TERM CARDIAC DAMAGE AND REMODELING KNOWN AS DOXORUBICIN CARDIOMYOPATHY. MOST STUDIES HAVE FOCUSED ON CARDIOMYOCYTES AS A DIRECT TARGET OF DOXORUBICIN. WE HAVE RECENTLY SHOWN THAT MICROVASCULAR ENDOTHELIUM IS A CRITICAL TARGET OF DOXORUBICIN IN THE HEART. SPECIFICALLY, WE DETECTED AN ALTERED PATTERN OF ENDOTHELIAL GENE EXPRESSION AND ADVERSE CARDIAC REMODELING THAT PERSISTED AFTER COMPLETION OF THE DOXORUBICIN TREATMENT AND WAS MEDIATED BY THE CANONICAL TGF- BETA PATHWAY. WHILE WE HAVE ESTABLISHED INVOLVEMENT OF THE TGF-BETA/SMAD3 PATHWAY IN ENDOTHELIAL DAMAGE BY DOXORUBICIN, THE DOWNSTREAM PROCESSES REMAIN UNKNOWN. ADDITIONALLY, MOST OF EXPERIMENTAL STUDIES ON DOXORUBICIN CARDIOTOXICITY HAVE BEEN PERFORMED ON MALE ANIMALS AND SEX-SPECIFIC DIFFERENCES IN PREVALENCE AND MECHANISMS OF CARDIOMYOPATHY HAVE NOT BEEN ADEQUATELY ADDRESSED. WE PROPOSE TO TEST A HYPOTHESIS THAT DOXORUBICIN PROMOTES ENDOTHELIAL REPROGRAMMING VIA UPREGULATION OF THE TGF-BETA/SMAD3 PATHWAY, AND SUPPRESSION OF SMAD3 TRANSCRIPTIONAL ACTIVITY IN ENDOTHELIAL CELLS WILL ALLEVIATE ENDOTHELIAL REPROGRAMMING AND CARDIOMYOPATHY IN DOXORUBICIN TREATED ANIMALS. SPECIFIC AIM 1 IS DESIGNED TO ASSESS THE ROLE OF THE TGF- BETA/SMAD3 PATHWAY IN ENDOTHELIAL-TO-MESENCHYMAL REPROGRAMMING BY DOXORUBICIN IN FEMALE AND MALE ENDOTHELIA. WE PLAN TO UTILIZE SMAD3 DEFICIENT HUMAN ENDOTHELIAL CELL LINES AND TRANSGENIC MOUSE STRAINS TO EXAMINE THE ROLE OF THIS PATHWAY IN BOTH ACTIVATION OF THE MESENCHYMAL/PROFIBROTIC PROGRAM AND SUPPRESSION OF ENDOTHELIUM SPECIFIC TRANSCRIPTION BY DOXORUBICIN. IN SPECIFIC AIM 2, WE PROPOSE TO EXAMINE THE ROLE OF ENDOTHELIAL SMAD3 IN PROMOTING ADVERSE CARDIOVASCULAR REMODELING AND DYSFUNCTION IN DOXORUBICIN TREATED FEMALE AND MALE MICE. WHILE OUR PRIOR STUDIES UTILIZED A MODEL OF GLOBAL SMAD3 KNOCKOUT, WE HAVE NOW GENERATED A NOVEL TRANSGENIC STRAIN FEATURING AN ENDOTHELIAL SMAD3 KNOCKOUT THAT WILL ENABLE US TO DIRECTLY ADDRESS THE ROLE OF CARDIAC ENDOTHELIAL CELLS IN DOXORUBICIN CARDIOMYOPATHY. WE PROPOSE TO UTILIZE A CLINICALLY RELEVANT MODEL OF DOXORUBICIN CARDIOMYOPATHY IN FEMALE AND MALE MICE THAT WILL ALLOW US TO EVALUATE THE ROLE OF ENDOTHELIAL SMAD3 IN SUSTAINED ENDOTHELIAL DYSFUNCTION, MICROVASCULAR REMODELING, AND DEPRESSED CARDIAC FUNCTION. STUDENTS AT THE COLLEGES OF OSTEOPATHIC MEDICINE AND BIOSCIENCES AT KCU WILL BE INVOLVED IN THE PROPOSED RESEARCH PROJECT. WE ANTICIPATE THAT THE PROPOSED APPROACH WILL HELP DEVELOP NOVEL VASCULATURE TARGETED THERAPIES TO PRESERVE ENDOTHELIAL RESILIENCY AND PREVENT CARDIAC REMODELING AND PROGRESSION OF CARDIOMYOPATHY.

EDUCATION STABILIZATION FUND: HIGHER EDUCATION RELIEF AID

COLLABORATIVE RESEARCH: INTEGRATIVE ANALYSIS OF INGESTIVE BIOMECHANICS AND DENTAL MICROWEAR IN EVOLUTIONARY AND ECOLOGICAL CONTEXT

COLLABORATIVE RESEARCH: INTEGRATIVE ANALYSIS OF HOMINID FEEDING BIOMECHANICS

COLLABORATIVE RESEARCH: CONSERVATION AND ECOLOGY OF THE TONKIN SNUB-NOSED MONKEY AT KHAU CA, HA GIANG PROVINCE, VIETNAM

A SUSTAINABLE MECHANISM FOR SUPPORTING YOUTH PHYSICAL ACTIVITY IN LOW-INCOME, MINORITY NEIGHBORHOODS