Despite improvements in worldwide health and advances in medical practice the incidence of preterm birth continues to rise in virtually every region of the globe and is accounts for nearly 15% of all live births in the United States. Associated with this increased population of very low birth-weight infants are several medical conditions that are both life threatening and costly. One of these conditions is necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. An important feature of this application is the investigation of nicotinamide (known inhibitor of PARP) as a potential therapeutic agent for NEC. We will carry out preclinical studies to define mechanistic actions and identify optimal conditions for potential efficacy. These studies will use relevant human fetal intestinal epithelial cells and animal models of newborn intestinal injury to test our working hypothesis. Our Phase 1 aims are: AIM 1: Define concentration-effect relationships and signaling activities of Nicotinamide using a preclinical model of human neonatal enterocyte injury and restitution and AIM 2: Evaluate the safety of and dosing regimen for nicotinamide in our established rat model of NEC and demonstrate proof of principle for attenuation of intestinal injury in our established newborn rat model of NEC by Nicotinamide. The specific goal of this phase 1 project is to demonstrate the proof of principle for the use of nicotinamide for NEC prevention and/or treatment.
Public Health Relevance: Despite improvements in worldwide health and advances in medical practice the incidence of preterm birth continues to rise in virtually every region of the globe and is accounts for nearly 15% of all live births in the United States. Associated with this increased population of very low birth-weight infants are several medical conditions that are both life threatening and costly. One of these conditions is necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. We have preliminary evidence to demonstrate that nicotinamide is a potential therapeutic agent for NEC. We will carry out preclinical studies to define mechanistic actions and identify optimal conditions for potential efficacy using relevant human fetal intestinal epithelial cells and animal models of newborn intestinal injury.
Public Health Relevance Statement: Despite improvements in worldwide health and advances in medical practice the incidence of preterm birth continues to rise in virtually every region of the globe and is accounts for nearly 15% of all live births in the United States. Associated with this increased population of very low birth-weight infants are several medical conditions that are both life threatening and costly. One of these conditions is necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. We have preliminary evidence to demonstrate that nicotinamide is a potential therapeutic agent for NEC. We will carry out preclinical studies to define mechanistic actions and identify optimal conditions for potential efficacy using relevant human fetal intestinal epithelial cells and animal models of newborn intestinal injury.
Project Terms: 0-6 weeks old; 3-Pyridinecarboxamide; ADP-Ribosyltransferase (Polymerizing); Accounting; Animal Model; Animal Models and Related Studies; Animals; Apoptosis; Apoptosis Pathway; Area; Assay; Bioassay; Biologic Assays; Biological Assay; Biology; Blood Chemical Analysis; Body Tissues; Businesses; Cell Communication and Signaling; Cell Death; Cell Death, Programmed; Cell Signaling; Cell Survival; Cell Viability; Cells; Chemical Analyses, Blood; Childhood; Common Rat Strains; Complementary therapies; Consumption; DNA Damage; DNA Damage Repair; DNA Injury; DNA Repair; Development; Development and Research; Disease; Disorder; Dose; Drugs; EC 1.14.13.39; EDRF Synthase; Endogenous Nitrate Vasodilator; Endothelium-Derived Growth Factor Synthase; Endothelium-Derived Relaxing Factor; Enterocytes; Epithelial; Epithelial Cells; Future; Gatekeeping; Goals; Guanylyl Cyclase-Activating Factor Synthase; Health; Healthcare Systems; Histopathology; Human; Human, General; Incidence; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Injury; Intensive Care Units, Neonatal; Intestinal; Intestines; Intracellular Communication and Signaling; Investigation; Investigators; L-Arginine,NADPH[{..}]oxygen oxidoreductase (nitric-oxide-forming); Lead; Life; Live Birth; Mammals, Rats; Man (Taxonomy); Man, Modern; Marketing; Mediator; Mediator of Activation; Mediator of activation protein; Medical; Medical Specialities; Medication; Medicine; Methods; Modeling; Mononitrogen Monoxide; Morbidity; Morbidity - disease rate; Morphology; Mortality; Mortality Vital Statistics; NAD+[{..}]poly(adenosine diphosphate D-ribose)-acceptor ADP-D-ribosyltransferase; NADPH-Diaphorase; NO Synthase; Necrosis; Necrotic; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Neonatology; Newborn Infant; Newborn Intensive Care Units; Newborns; Niacinamide; Nicotinamide; Nicotinamidum; Nicotinic acid amide; Nicotylamide; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide, Endothelium-Derived; Nitric-Oxide Synthetase; Nitrogen Monoxide; Nitrogen Protoxide; Nitrogen oxide; Operation; Operative Procedures; Operative Surgical Procedures; PARP Polymerase; PARP inhibition; PARS; Pathogenesis; Pathway interactions; Pb element; Pellagra-Preventing Factor; Perforation; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacology; Phase; Play; Poly(ADP-Ribose) Synthase; Poly(ADP-Ribose) Transferase; Poly(ADP-ribose) Polymerases; Poly(ADPR) Polymerase; Poly(ADPribose) Polymerase; Population; Position; Positioning Attribute; Pre-Clinical Model; Preclinical Models; Premature Birth; Premature Infant; Preterm Birth; Prevention; Proteins; Protocols, Treatment; R & D; R&D; RGM; Rat; Rattus; Reactive Nitrogen Species; Regimen; Research; Research Personnel; Researchers; Role; Route; STTR; Safety; Science of Medicine; Screening procedure; Secondary to; Signal Transduction; Signal Transduction Systems; Signaling; Small Business Technology Transfer Research; Specialties, Medical; Specialty; Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; Systems, Health Care; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicities; Treatment Protocols; Treatment Regimen; Treatment Schedule; United States; Unscheduled DNA Synthesis; Very Low Birth Weight Infant; Villus; Vitamin B 3; Vitamin B3; Vitamin PP; Work; attenuation; base; biological signal transduction; blood chemistry; bowel; disease/disorder; drug/agent; endothelial cell derived relaxing factor; experiment; experimental research; experimental study; fetal; functional outcomes; gatekeeper; gene product; heavy metal Pb; heavy metal lead; high risk; improved; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; medical specialties; model organism; necrocytosis; neonatal human; newborn human (0-6 weeks); novel; oxidation; pathway; pediatric; poly ADP polymerase; poly ADP ribose synthetase; pre-clinical; preclinical; preclinical study; premature baby; premature childbirth; premature delivery; premature infant human; preterm baby; preterm delivery; preterm infant; preterm infant human; preterm neonate; public health relevance; research and development; research study; response; screening; screenings; social role; surgery; very low birth weight infant human
