Role of Creatine Metabolism in Necrotizing Enterocolitis

肌酸代谢在坏死性小肠结肠炎中的作用

• 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
• 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

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.

项目总结 坏死性小肠结肠炎(NEC)是一种新生儿期炎症性胃肠道疾病，其发病机制尚不明确。 而且可能是多因素的，发病机制。NEC最常影响早产、极低出生体重(VLBW，&lt；1500克) 婴儿，以及包括生态失调、配方奶喂养和早产在内的危险因素都与NEC有关 病因学。我们的长期目标是确定促进出生后肠道弹性的营养策略 环境、发育和微生物的影响增加了对NEC的敏感性。肌酸(肌酸)是 一种氨基酸衍生物，具有抗氧化、抗炎和生物能量方面的许多好处 各种各样的疾病。在炎症性肠病(IBD)期间，铬的产生或摄取减少促进 肠上皮细胞(IEC)功能障碍，同时补充铬稳定肠屏障功能，改善 生物能量学，加速伤口愈合。虽然胎儿的铬是通过母体转移提供的，但婴儿必须 出生后内源性合成铬，因为母乳和婴儿配方奶粉中的铬含量可以忽略不计。在……里面 早产儿，由于早产，功能不成熟，缺乏晚期妊娠营养的积累 负责内源合成的酶系统，以及由于快速生长和 新生儿期的发育可能使铬成为一种有条件的基本营养物质，在这种情况下 婴儿可能有动态平衡方面的缺陷。间歇性缺氧期，一种常见的成熟后果 早产和急性肠炎的发展可能进一步延长对铬的需求 在这群人中。我们的初步数据表明，铬可加速创伤后肠上皮的修复 并抑制caspase3/7诱导的早产儿人肠样NEC模型的细胞凋亡 炎症性损伤。该项目将检验(目标1)铬缺乏对早产有害影响的假设 婴儿肠上皮损伤，而补充铬可防止NEC样损伤，(目标2)铬 代谢与早产儿NEC的发展双向相关，早产儿尿铬水平低 婴儿是系统性低铬储存和/或高组织铬利用率以及肠道铬耗竭的代用品 与NEC的发展相联系。该项目的成功完成将带来一种新的治疗方法 NEC的目标，这是一种目前没有有效的预防母乳替代品的情况，以及 除了手术干预和支持性护理之外，没有有效的治疗方法，使用已经注意到的补充剂 在早产人群中要有很好的耐受性。