R01DK143079

NOVEL MACROPHAGE MEDIATED SIGNALS REGULATE THE IMMUNOREGULATORY ENVIRONMENT OF THE NEONATAL LIVER - PROJECT SUMMARY THE BALANCE BETWEEN REGULATORY AND IMMUNOGENIC IMMUNE RESPONSES IS CRITICAL FOR LIVER HOMEOSTASIS DURING PERINATAL LIFE BECAUSE DYSREGULATION OF EITHER CAN LEAD TO CHRONIC VIRAL INFECTION FROM SUSTAINED IMMUNE SUPPRESSION (AS IN CHRONIC NEONATAL HEPATITIS B) OR, TO NEONATAL CIRRHOSIS FROM UNMITIGATED INFLAMMATION (AS IN BILIARY ATRESIA). IT IS THEREFORE ESSENTIAL TO UNDERSTAND THE MECHANISMS THAT MAINTAIN THE DELICATE BALANCE BETWEEN REGULATORY IMMUNE RESPONSES AND IMMUNITY IN THE PERINATAL LIVER AS DEVASTATING SEQUELAE OF EITHER TOO MUCH IMMUNE SUPPRESSION, IN THE CASE OF CHRONIC NEONATAL HEPATITIS B, OR TOO MUCH IMMUNITY, IN THE CASE OF BILIARY ATRESIA, LEADS TO SIGNIFICANT MORBIDITY. IN THIS PROPOSAL, WE WILL INVESTIGATE THE ROLE OF THE SCAVENGER RECEPTOR MARCO IN MAINTAINING THIS CRUCIAL BALANCE BETWEEN REGULATION AND IMMUNITY IN THE PERINATAL LIVER. SCAVENGER RECEPTORS ARE CELL SURFACE RECEPTORS FOUND ON PHAGOCYTIC IMMUNE CELLS, AND ARE IMPORTANT MEDIATORS OF IMMUNE HOMEOSTASIS, INFLAMMATION, AND TOLERANCE. WE HAVE IDENTIFIED AN IMPORTANT ROLE FOR THE CLASS A SCAVENGER RECEPTOR MARCO EXPRESSED ON MACROPHAGES IN TUNING IMMUNOREGULATORY RESPONSES AND INFLAMMATION IN THE PERINATAL LIVER. OUR PRELIMINARY DATA INDICATES THAT MARCO IS HIGHLY EXPRESSED ON MOUSE AND HUMAN LIVER MACROPHAGES, RESTRICTS ANTI-INFLAMMATORY MYELOID CELLS, AND WORSENS OUTCOMES IN A MOUSE MODEL OF PERINATAL LIVER INFLAMMATION. OUR DATA ALSO SUPPORT THE IDEA THAT MARCO RESTRICTS ANTI-INFLAMMATORY FUNCTIONS OF MACROPHAGES BY LIMITING RESPONSIVENESS TO THE POTENT ANTI-INFLAMMATORY CYTOKINE INTERLEUKIN-10 (IL-10). WE THEREFORE HYPOTHESIZE THAT MARCO RESTRICTS REGULATORY/ANTI-INFLAMMATORY IMMUNE RESPONSES BY INHIBITING RESPONSIVENESS TO IL-10. TO ADDRESS THIS HYPOTHESIS, WE WILL USE NOVEL TOOLS THAT INVOLVE TECHNICALLY CHALLENGING PORTAL VEIN INJECTIONS OF A MODEL ANTIGEN TO QUANTIFY ENDOGENOUS ANTIGEN-SPECIFIC IMMUNE RESPONSES IN NEONATAL LIVER AND A CRISPR-CAS9 BASED METHOD TO ABLATE MARCO IN PRIMARY HUMAN MACROPHAGES. ALONG WITH OUR ESTABLISHED MODEL OF PERINATAL LIVER INFLAMMATION, WE WILL USE THESE TOOLS TO ADDRESS THE FOLLOWING SPECIFIC AIMS: AIM 1: DETERMINE WHETHER MARCO RESTRICTS IMMUNOREGULATORY RESPONSES BY DIRECTLY INHIBITING THE IL-10 RECEPTOR; AIM 2: DETERMINE WHETHER MARCO INHIBITS ANTIGEN-SPECIFIC REGULATORY RESPONSES IN THE LIVER; AIM 3: TEST WHETHER MARCO LIMITS RESOLUTION OF PERINATAL LIVER INFLAMMATION BY INHIBITING ANTI-INFLAMMATORY MONOCYTES. COMPLETION OF THE PROPOSED AIMS WILL DEFINE THE ROLE OF MARCO IN PERINATAL HEPATIC IMMUNE FUNCTION AND WILL YIELD IMPORTANT INSIGHTS INTO HOW MACROPHAGE-MEDIATED IMMUNE SIGNALS MAINTAIN THE BALANCE BETWEEN IMMUNE REGULATION AND IMMUNITY IN THE DEVELOPING LIVER. UNDERSTANDING THESE SIGNALS IS CRITICAL TO ELUCIDATING THE PATHOGENESIS OF HIGHLY MORBID LIVER DISEASES IN PEDIATRIC PATIENTS AND IS THE NEXT IMPORTANT STEP FOR BEING ABLE TO DESIGN POTENTIAL THERAPIES.

San Francisco Regents Of The University Of California

(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]

San Francisco, California 94143 United States

Single Zip Code

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