R01DK144139

MECHANISMS OF AGE-AND SEX- DEPENDENT CHANGES IN URINARY BLADDER IMMUNITY - PROJECT SUMMARY URINARY TRACT INFECTIONS (UTIS) EXHIBIT ONE OF THE MOST SIGNIFICANT SEX DISPARITIES AMONG INFECTIOUS DISEASES WITH UTIS IN WOMEN BEING 20-40 TIMES MORE LIKELY THAN IN MEN. IN ADDITION, 25-50% OF ELDERLY WOMEN SUFFER FROM RECURRENT UTIS (RUTIS) DESPITE TAKING ANTIBIOTICS, AND OVER 25% OF ALL ELDERLY WOMEN EXPERIENCE PERSISTENT INFLAMMATION AND LOWER URINARY TRACT CONDITIONS SUCH AS OVERACTIVE BLADDER/URGE INCONTINENCE AND INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME. GIVEN THE STRONG ASSOCIATION BETWEEN BLADDER DISEASES AND AGING, AND THE FACT THAT CHRONIC BLADDER INFLAMMATION IS HIGHLY PREVALENT IN OLDER WOMEN, AGE-ASSOCIATED IMMUNE DISRUPTION (SO- CALLED INFLAMM-AGING) IN THE BLADDER LIKELY MEDIATES RUTI SUSCEPTIBILITY. WITH 566 MILLION PEOPLE ≥65 YEARS OLD WORLDWIDE AND ESTIMATES OF NEARLY 1.5 BILLION BY 2050, THERE IS A GROWING NEED TO DEFINE THE INTERACTIONS BETWEEN AGING, CHRONIC INFLAMMATION, AND SUSCEPTIBILITY TO UTIS/RUTIS SO THAT BETTER TREATMENTS AND PREVENTION OF THESE DISEASES WILL BE POSSIBLE. THE HYPOTHESIS OF THIS PROJECT IS THAT THE CULPRIT BEHIND MANY RUTI CASES AND LOWER URINARY TRACT SYMPTOMS IS A CHRONIC INFLAMMATORY PROCESS CHARACTERIZED BY ORGANIZED LYMPHOCYTIC AGGREGATES IN THE BLADDER SUBMUCOSA, TERMED BLADDER TERTIARY LYMPHOID TISSUE (BTLT). THESE ARE ANALOGOUS TO LYMPHOCYTIC INFILTRATES IN WOMEN PRESENTING AS CYSTITIS CYSTICA (CC) BY CYSTOSCOPY. WE HAVE DEMONSTRATED THAT BTLT/CC ARE PREDOMINANTLY IN WOMEN AND FEMALE MICE AND ARE SITES OF ANTIGEN PRESENTATION, GERMINAL CENTER FORMATION, AND ANTIBODY PRODUCTION, AND FORM IN AN AGE-DEPENDENT AND SEX-DEPENDENT MANNER. DESPITE THIS UNDERSTANDING, THE MECHANISMS DRIVING BTLT FORMATION, MAINTENANCE, IMPACT ON RUTIS, AND SEX DEPENDENCE ARE UNKNOWN. USING A MOUSE MODEL OF AGING AND CHRONIC BLADDER INFECTION AND INFLAMMATION THAT CLOSELY PARALLELS THE CLINICAL PRESENTATION OF POST-MENOPAUSAL WOMEN WITH UTIS, WE WILL ELUCIDATE THE UNDERLYING IMMUNE AND HORMONAL DRIVERS THAT CAUSE FREQUENT RECURRENT UTIS AND HEIGHTENED LOWER URINARY TRACT SYMPTOMS IN A SEX-DEPENDENT MANNER. SPECIFICALLY, WE WILL DEFINE THE MOLECULAR DRIVERS (AIM 1) AND INVESTIGATE THE ROLE OF CXCL13, TNFΑ, AND FCRL5 IN BTLT INITIATION, MAINTENANCE, AND STRUCTURE WILL BE INVESTIGATED THROUGH TARGETED INTERVENTIONS IN AGED MICE; EXPLORE THE ROLE OF BTLT IN IMMUNE RESPONSES DURING UTI BY DEPLETING B CELLS AND PROFILING B CELL RECEPTOR REPERTOIRES, IDENTIFYING CLONOTYPES INVOLVED IN UTI DEFENSE. (AIM 2); DETERMINE THE CAUSE-AND-EFFECT ASSOCIATION BETWEEN BTLT/CC AND RUTIS; AND DEFINE THE INFLUENCE OF SEX AND ESTROGEN ON BTLT FORMATION (AIM 3). THIS NEW CONCEPT OF THE INTERPLAY BETWEEN AGING, SEX, INFECTION, AND LOCAL IMMUNE RESPONSES WITHIN THE BLADDER GENERATES MANY NEW IMPORTANT QUESTIONS FOR THE FIELD. BY ELUCIDATING THE MECHANISMS, MEDIATORS, AND TRIGGERS THAT DRIVE BTLT FORMATION, TAKING INTO CONSIDERATION SEX DIFFERENCES, THIS WORK WILL PROVIDE IMPORTANT INSIGHTS INTO MUCOSAL IMMUNITY IN THE AGING BLADDER. ADDITIONALLY, THIS WORK WILL ESTABLISH THE FOUNDATION FOR FUTURE DEVELOPMENT OF BIOMARKERS OF FUNCTIONAL IMMUNE SYSTEM CHANGES IN OLDER INDIVIDUALS TO GUIDE TREATMENT STRATEGIES AIMED AT IMPROVING INFECTION AND INFLAMMATION OUTCOMES.

Baylor College Of Medicine

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Texas United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)