R01DK142076

ROLE OF NEUTROPHILS IN THE PATHOGENESIS OF CHOLANGIOPATHIES - CHOLANGIOPATHIES ARE RESPONSIBLE FOR SIGNIFICANT MORBIDITY AND MORTALITY BUT REMAIN THE LEAST UNDERSTOOD DISEASES IN HEPATOLOGY. CHOLANGIOCYTES ARE THE MAIN CELLULAR TARGET IN CHOLANGIOPATHIES AND IN RESPONSE TO DAMAGE OR INFLAMMATION, THEY ASSUME A REACTIVE PHENOTYPE, GENERATE PRO-INFLAMMATORY MEDIATORS AND CYTO-CHEMOKINES, PROLIFERATE, REDUCE THEIR SECRETORY FUNCTION, AND FURTHER AMPLIFY THE INFLAMMATORY RESPONSES. THE INFLAMMATORY MICROENVIRONMENT IN CHOLANGIOPATHIES IS POPULATED BY SEVERAL CELL TYPES THAT COMMUNICATE WITH EACH OTHER AND WITH CHOLANGIOCYTES. THIS COMPLEX CELLULAR NETWORK IS STILL POORLY UNDERSTOOD AND EXHIBITS DISEASE-SPECIFIC ASPECTS THAT MAY ULTIMATELY BE RELEVANT FOR THERAPY. AMONG THE INFLAMMATORY CELLS INFILTRATING THE PORTAL SPACE, NEUTROPHILS HAVE RECEIVED LITTLE ATTENTION. SOME DISORDERS AFFECTING BILE DUCTS RESULT IN SIGNIFICANT INFILTRATION OF NEUTROPHILS INTO THE PORTAL REGION, BUT THE PATHOPHYSIOLOGICAL CONSEQUENCES REMAIN UNKNOWN. THE FIELD OF NEUTROPHIL BIOLOGY HAS RECENTLY ADVANCED IN A FUNDAMENTAL WAY. THERE IS NOW A RECOGNITION THAT SOME NEUTROPHILS ARE ATTRACTED TO AND THEN REPROGRAMMED BY TISSUES IN AN ORGAN-SPECIFIC FASHION. IN CONTRAST TO THOSE IN THE BLOODSTREAM, THESE INFILTRATING NEUTROPHILS OFTEN LIVE DAYS LONGER IN TARGET TISSUES, WHERE THEY GO ON TO SERVE NONDESTRUCTIVE ROLES SUCH AS REGULATION OF METABOLISM, SECRETION, ANGIOGENESIS, AND PROLIFERATION. ALTHOUGH THESE NON-TRADITIONAL ROLES FOR NEUTROPHILS HAVE NOT YET BEEN STUDIED IN CHOLANGIOPATHIES, IN PART DUE TO DIFFICULTIES (THAT WE HAVE OVERCOME) IN ISOLATING NEUTROPHILS FROM LIVER IN SUFFICIENT AMOUNTS FOR SINGLE CELL TRANSCRIPTOMIC ANALYSIS. OUR PRELIMINARY EVIDENCE SUGGESTS THAT PERIDUCTULAR NEUTROPHILS ARE LARGELY DISTINCT FROM THOSE OF NEUTROPHILS IN THE BLOODSTREAM. WE ALSO HAVE GENERATED PRELIMINARY EVIDENCE TO SUGGEST THAT CHOLANGIOCYTES SECRETE CYTOKINES/CHEMOKINES AS ‘HOMING SIGNALS’ TO ATTRACT AND THEN REPROGRAM NEUTROPHILS, AND THESE HOMING SIGNALS MAY DIFFER DEPENDING ON THE CHOLANGIOPATHY. TO MAKE THESE OBSERVATIONS, WE HAVE DEVELOPED SEVERAL METHODS FOR RECOVERING NEUTROPHILS FROM THE LIVER AND FROM THE BILIARY TREE IN SUFFICIENT AMOUNTS TO PERFORM SCRNA-SEQ. BASED ON EXTENSIVE NEW PRELIMINARY DATA, WE HYPOTHESIZE THAT NEUTROPHILS PLAY A MAJOR ROLE IN THE PATHOGENESIS OF CHOLANGIOPATHIES BY BEING ATTRACTED BY CHOLANGIOCYTES, WHICH REPROGRAM THE NEUTROPHILS TO AMPLIFY THE INFLAMMATORY RESPONSE AND TO INTERACT WITH CHOLANGIOCYTES RESULTING IN CHOLESTASIS, CHANGES IN TRANSCRIPTOME AND ALTERED PROLIFERATION IN A CONDITION--SPECIFIC WAY. THE NONTRADITIONAL ROLES FOR NEUTROPHILS BEING PROPOSED HERE WILL BE PARADIGM-SHIFTING IN TERMS OF HOW WE UNDERSTAND THE ROLE OF NEUTROPHILS IN BILIARY DISEASES. FURTHERMORE, WE WILL ADVANCE THE FIELD OF NEUTROPHIL BIOLOGY AS WELL, BY PROVIDING EVIDENCE NOT ONLY THAT TRANSCRIPTOMIC SIGNATURES OF NEUTROPHILS IN THE LIVER DIFFER FROM THOSE IN THE BLOOD, THAT THESE SIGNATURES IN THE LIVER MAY BE DISEASE-SPECIFIC AND THAT THE INTERACTIONS BETWEEN CHOLANGIOCYTES AND NEUTROPHILS ARE TARGETS OF POTENTIAL THERAPEUTIC RELEVANCE.

Yale Univ

(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]

Connecticut United States

State-Wide

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