Role of Transforming Growth Factor-beta in Neonatal Necrotizing Enterocolitis

转化生长因子-β 在新生儿坏死性小肠结肠炎中的作用

• 批准号: 7532407
• 负责人: Akhil Maheshwari
• 金额: $ 32.76万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-28 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532407
• 关键词: Acute; Adenoviruses; Adult; Affect; Asphyxia; Bacteria; Bacterial Translocation; Bifidobacterium; Cause of Death; Cells; Chad; Characteristics; Clinical Research; Conditioned Culture Media; Data; Development; Disease; Dominant-Negative Mutation; Down-Regulation; Ecology; Enteral; Escherichia coli; Etiology; Extracellular Matrix; Figs - dietary; Funding Opportunities; Future; Gastrointestinal Diseases; Gelatinase A; Germ-Free; Gestational Age; Gnotobiotic; Goals; Hospitals; Human; Human Milk; Immune; Infant; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Injury; Intervention; Intestinal Mucosa; Intestines; Investigation; Ischemic Bowel Disease; Laboratories; Lactobacillus; Lamina Propria; Leukocytes; Life; London; Measures; Mediator of activation protein; Methodology; Milk; Modeling; Morbidity - disease rate; Mothers; Mucositis; Mus; Necrosis; Necrotizing Enterocolitis; Neonatal; Nurses; Pathway interactions; Patients; Pattern; Peptides; Permeability; Phosphotransferases; Platelet Activating Factor; Predisposition; Pregnancy Trimesters; Premature Infant; Prevention; Preventive; Probiotics; Production; Protein Isoforms; Protocols documentation; Reaction; Recombinant Transforming Growth Factor; Recombinants; Reporting; Research; Research Personnel; Role; Rosa; Sampling; Severities; Signal Transduction; Stromal Cells; Supplementation; TNF gene; Testing; Therapeutic; Tissue Sample; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Tretinoin; Up-Regulation; Wild Type Mouse; base; cytokine; design; feeding; fetal; in vitro Model; insight; macrophage; monocyte; mortality; natural hypothermia; neonate; novel; premature; prevent; prophylactic; public health relevance; pup; receptor; recombinant virus; research study

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is an acquired, life-threatening gastrointestinal disease affecting 5-15% of neonates born weighing less than 1500 g and is a leading cause of death in these patients. The disease is characterized by an intense inflammatory response, ischemic changes, and necrosis. Although the etiopathogenesis of NEC is not well understood, the disease is believed to occur when mucosal injury or altered permeability allows bacterial translocation into the lamina propria, causing leukocyte recruitment and tissue destruction. This model of unrestricted acute inflammation due to bacteria/bacterial products is inconsistent with recent observations that in the adult, intestinal cells such as macrophages are profoundly `anergic' to bacterial products due to the effect of stromal cell-derived factors such as transforming growth factor (TGF)-2. The investigators present preliminary data and propose a novel hypothesis that NEC is seen almost exclusively in the premature infant because mucosal tolerance to bacterial products, which is due to the effects of TGF-2, is developmentally regulated and therefore deficient in the preterm intestine, and that augmentation of TGF-2 expression or bioactivity can prevent/ameliorate NEC-like intestinal injury. This application is designed to investigate strategies to augment TGF-2 activity in the developing intestine in order to enhance mucosal tolerance to bacterial products. There are three specific aims: 1) to determine whether specific patterns of bacterial colonization of the neonatal intestinal mucosa affect the normal developmental downregulation of inflammatory pathways in the intestinal mucosa or influence susceptibility to NEC-like intestinal injury; 2) to determine the role of milk-borne TGF-22 in protection against NEC-like intestinal injury, and whether enteral supplementation of TGF-22 in the neonate can provide additional protection against NEC-like intestinal injury; and 3) to determine whether pharmacological upregulation of TGF-22 expression or activation in the developing intestine can protect against NEC-like intestinal injury. The long-term goals of this project are to identify newer preventive/therapeutic strategies against NEC that can be tested in future clinical studies. PUBLIC HEALTH RELEVANCE: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely premature infants. In this application, the investigators present a novel hypothesis that NEC occurs almost exclusively in premature infants because normal tolerance to gut bacteria is not yet established in these infants and propose three different strategies to correct this deficiency, which can, in turn, help prevent or treat NEC.

描述（由申请人提供）：坏死性小肠结肠炎 (NEC) 是一种后天性危及生命的胃肠道疾病，影响 5-15% 的出生体重低于 1500 克的新生儿，并且是这些患者死亡的主要原因。该疾病的特征是强烈的炎症反应、缺血性变化和坏死。尽管 NEC 的发病机制尚不清楚，但据信当粘膜损伤或渗透性改变导致细菌易位至固有层，导致白细胞募集和组织破坏时，就会发生该疾病。这种由细菌/细菌产物引起的不受限制的急性炎症模型与最近的观察结果不一致，即在成人中，由于转化生长因子（TGF）-2等基质细胞衍生因子的影响，巨噬细胞等肠道细胞对细菌产物极度“无反应”。研究人员提供了初步数据并提出了一个新的假设，即 NEC 几乎只见于早产儿，因为由于 TGF-2 的作用，粘膜对细菌产物的耐受性是发育调节的，因此在早产儿肠道中存在缺陷，而 TGF-2 表达或生物活性的增强可以预防/改善 NEC 样肠道损伤。该应用旨在研究增强发育中肠道中 TGF-2 活性的策略，以增强粘膜对细菌产物的耐受性。有三个具体目标：1）确定新生儿肠粘膜细菌定植的特定模式是否影响肠粘膜炎症途径的正常发育下调或影响对NEC样肠损伤的易感性； 2) 确定乳源性TGF-22在预防NEC样肠道损伤中的作用，以及新生儿肠内补充TGF-22是否可以提供针对NEC样肠道损伤的额外保护； 3) 确定发育中肠道中 TGF-22 表达或激活的药理学上调是否可以预防 NEC 样肠道损伤。该项目的长期目标是确定针对 NEC 的新预防/治疗策略，并可在未来的临床研究中进行测试。公共卫生相关性：坏死性小肠结肠炎 (NEC) 是极早产儿发病和死亡的主要原因。在本申请中，研究人员提出了一个新的假设，即 NEC 几乎只发生在早产儿中，因为这些婴儿尚未建立对肠道细菌的正常耐受性，并提出了三种不同的策略来纠正这种缺陷，从而有助于预防或治疗 NEC。