Role of Creatine Metabolism in Necrotizing Enterocolitis

肌酸代谢在坏死性小肠结肠炎中的作用

基本信息

批准号：
10724729
负责人：
Kathryn Young Burge
金额：
$ 39.88万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-05 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724729
关键词：
Acceleration Acute Adult Affect Amino Acids Anti-Inflammatory Agents Antioxidants Apical Arginine Athletic Bioenergetics Biological Biological Assay Biological Markers Biopsy Blood Vessels Buffers CASP3 gene Cells Cessation of life Characteristics Colon Constipation Creatine Data Development Dietary intake Disease Disease model Distal Emergency Situation Enzymes Epithelial Cells Etiology Functional disorder Future Gastrointestinal Diseases Genus Hippocampus Glycine Goals Growth Growth and Development function Guanidinoacetate N-Methyltransferase Homeostasis Human Human Milk Hypoxia Ileus Immune response Immunohistochemistry Impairment Inborn Errors of Metabolism Incidence Induction of Apoptosis Infant Infant formula Inflammation Inflammatory Inflammatory Bowel Diseases Inhibition of Apoptosis Injury Intestines Invaded Length of Stay Life Malnutrition Measures Metabolic Metabolic stress Metabolism Mitochondria Modeling Multiple Organ Failure Natural Products Necrosis Necrotizing Enterocolitis Nutrient Nutritional Observational Study Oklahoma Operative Surgical Procedures Pathogenesis Pathology Pediatric Hospitals Permeability Phosphocreatine Phosphotransferases Physiological Processes Population Predisposition Premature Birth Premature Infant Production Proxy Recycling Resolution Respiration Risk Factors Role Runaway Safety Severities Small Intestines Societies Source Supplementation Supportive care System TLR4 gene Testing Therapeutic Third Pregnancy Trimester Tissues Urine Very Low Birth Weight Infant Western Blotting biobank cell motility creatine transporter dysbiosis effective therapy environmental stressor epithelial injury epithelial wound feeding fetal gastrointestinal guanidinoacetate gut inflammation improved in vitro Model insight intestinal barrier intestinal epithelium intestinal injury knock-down metabolomics monolayer neonatal period novel nutritional approach organic acid physiologic stressor postnatal pre-clinical premature prevent prophylactic protein expression rapid growth resilience skip lesion solute systemic inflammatory response therapeutic target therapeutically effective uptake wound wound healing

项目摘要

PROJECT SUMMARY Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease of the neonatal period with an unclear, and likely multifactorial, pathogenesis. NEC most often affects preterm, very low birthweight (VLBW, < 1500 g) infants, and risk factors including dysbiosis, formula feeding, and prematurity have been implicated in NEC etiology. Our long-term goal is to identify nutritional strategies promoting postnatal intestinal resilience to environmental, developmental, and microbiological influences increasing susceptibility to NEC. Creatine (Cr) is an amino acid derivative with demonstrated antioxidant, anti-inflammatory, and bioenergetic benefits in a number of diverse diseases. During inflammatory bowel disease (IBD), reduced Cr production or uptake promotes intestinal epithelial cell (IEC) dysfunction, while Cr supplementation stabilizes intestinal barrier function, improves bioenergetics, and accelerates wound healing. While fetal Cr is provided through maternal transfer, infants must endogenously synthesize Cr postnatally, as both human milk and infant formula contain negligible levels. In preterm infants, a lack of third trimester accretion of the nutrient due to premature birth, immature functionality of enzyme systems responsible for endogenous synthesis, and increased requirements due to rapid growth and development in the neonatal period likely render Cr a conditionally essential nutrient, and one in which these infants are likely deficient at homeostasis. Periods of intermittent hypoxia, a common maturational consequence of prematurity, and the development of acute intestinal inflammation could further extend the requirement for Cr in this population. Our preliminary data suggest Cr accelerates intestinal epithelial restitution following wounding and inhibits caspase 3/7-induced apoptosis in a preterm human intestinal enteroid model of NEC-like inflammatory injury. This project will test the hypotheses that (Aim 1) Cr deficiency detrimentally affects preterm infant intestinal epithelial injury, while Cr supplementation prevents NEC-like injury, and that (Aim 2) Cr metabolism is bidirectionally related to NEC development in preterm infants, with low urine Cr levels in preterm infants a proxy for systemically low Cr stores and/or high tissue Cr utilization, and intestinal Cr depletion associating with development of NEC. Successful completion of this project will introduce a novel treatment target for NEC, a condition for which there are currently no effective prophylactic alternatives to human milk, and no effective therapeutics beyond surgical intervention and supportive care, using a supplement already noted to be well-tolerated in the preterm population.

项目概要坏死性小肠结肠炎（NEC）是新生儿期的一种炎症性胃肠道疾病，其病因尚不明确。并且可能是多因素的发病机制。 NEC 最常影响早产、极低出生体重（VLBW，< 1500 g） NEC 涉及婴儿，包括菌群失调、配方奶喂养和早产在内的危险因素病因学。我们的长期目标是确定促进产后肠道恢复能力的营养策略环境、发育和微生物影响增加了 NEC 的易感性。肌酸 (Cr) 是一种氨基酸衍生物，在多种方面具有抗氧化、抗炎和生物能功效的多种疾病。在炎症性肠病 (IBD) 期间，铬的产生或吸收减少会促进肠上皮细胞 (IEC) 功能障碍，而补充 Cr 可以稳定肠道屏障功能，改善生物能量学，并加速伤口愈合。虽然胎儿 Cr 是通过母体移植提供的，但婴儿必须出生后内源合成 Cr，因为母乳和婴儿配方奶粉中的 Cr 含量可以忽略不计。在早产儿、由于早产而导致妊娠晚期缺乏营养、功能不成熟负责内源合成的酶系统，以及由于快速生长和增加的需求新生儿期的发育可能使 Cr 成为一种有条件的必需营养素，并且其中这些婴儿可能缺乏体内平衡。间歇性缺氧是成熟过程中常见的后果早产儿的发生以及急性肠道炎症的发展可能会进一步延长对 Cr 的需求在这个人群中。我们的初步数据表明 Cr 加速受伤后肠上皮的恢复并在 NEC 样早产人肠肠样模型中抑制 caspase 3/7 诱导的细胞凋亡炎症损伤。该项目将检验以下假设：（目标 1）Cr 缺乏对早产产生不利影响婴儿肠上皮损伤，而补充 Cr 可以预防 NEC 样损伤，并且（目标 2）Cr 代谢与早产儿 NEC 发育双向相关，早产儿尿 Cr 水平较低婴儿是全身低 Cr 储存和/或高组织 Cr 利用率以及肠道 Cr 消耗的指标与NEC的发展相关。该项目的成功完成将引入一种新的治疗方法 NEC 的目标，目前没有有效的母乳预防替代品，以及除了手术干预和支持性护理外，没有有效的治疗方法，使用已经注意到的补充剂在早产人群中具有良好的耐受性。