Mechanisms of Gastrointestinal Epithelial Cell Injury & Repair During Development

胃肠道上皮细胞损伤的机制

• 批准号: 8496009
• 负责人: Steven James McElroy
• 金额: $ 14.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496009
• 关键词: Acute; Adult; Affect; Age; Animal Model; Animals; Apoptosis; Attenuated; Birth; Cause of Death; Cellular biology; Chemoprevention; Data; Development; Developmental Biology; Disease; Down-Regulation; EGF gene; Epidermal Growth Factor Receptor; Epithelial Cells; Face; Fostering; Functional disorder; Gastrointestinal Diseases; Gastrointestinal tract structure; Genetic Models; Immunofluorescence Immunologic; Incidence; Infant; Infant Development; Inflammation; Inflammatory; Injury; Instruction; Intestines; Investigation; Laboratories; Life; Ligands; Link; Live Birth; Liver Failure; MAPK14 gene; Mentors; Morbidity - disease rate; Mus; Necrotizing Enterocolitis; Neurodevelopmental Disability; Newborn Infant; Outcome; Phosphorylation; Phosphorylation Site; Predisposition; Premature Infant; Prevention; Process; Publishing; Receptor Activation; Receptor Inhibition; Relative (related person); Resources; Risk; Role; Severity of illness; Signal Transduction; Small Intestines; Staging; Stream; Survivors; Techniques; Testing; Therapeutic; Time; Tissues; Training; Tumor Necrosis Factor-alpha; Western Blotting; Work; base; career development; cell growth; cell injury; computerized data processing; cytokine; feeding; gastrointestinal; in vivo; injury and repair; killings; migration; mortality; neonate; novel; novel therapeutic intervention; postnatal; premature; prevent; promoter; pup; receptor expression; receptor internalization; statistics

Premature infants face a host of unique issues due to their developmental immaturity. One of the most devastating is necrotizing enterocolitis (NEC), which yearly kills 12 babies per 100,000 live births in the USand frequently leaves survivors with severe feeding issues, liver failure, and neurodevelopmental disability. Understanding mechanisms of intestinal injury and repair in developing intestine is key to developing new prevention and therapeutic strategies for NEC. This proposal will investigate the mechanisms of gastrointestinal epithelial cell injury and repair duringdevelopment by testing the hypothesis that the intestine of premature infants and newborn mice is more susceptible to TNF-induced injury because of an ontogenically normal decrease in expression and activation of EGFR. This hypothesis will be examined through the following specific Aims: 1) Define the effects of TNF on intestinal injury and apoptosis at different developmental stages. This will be accomplished using histopathologic injury scores of early intestinal damage as well as immunofluorescence and immunohistochemicalassays for apoptosis; 2) Determine the effects of TNF on EGFR inhibition in neonates compared to adults. We will study the effects of TNFon multipleEGFR phosphorylation sites and down-stream targets, and the role of EGFR internalization in TNF-stimulatedEGFR inhibition. This aim willutilize immunofluorescence and western blot analysis to study the down-stream targets of EGFR activation; and 3) Determine the role of EGFR activation in protecting against TNFinduced injury using pharmacologic and genetic models of EGFR activation. This aim will build on techniques developed in Aim 1 and 2 and apply them to mice with constitutively active EGFR, pharmacologicallyactive EGFR, and deficiency of EGFR. Overall,these studies will reveal the roles of TNFand EGFR in intestinal injury processes in developing intestinal tissue, and will identify potential novel avenues oftherapy and chemoprevention. In addition to the above studies, this proposal will greatly enhance career development through didactic training in cell biology, developmental biology, and statistics; by providing mentoring from a strong laboratory; and by utilizing the strong resources uniquely available at Vanderbilt to foster independent investigation in gastrointestinal disease.

早产儿由于发育不成熟而面临许多独特的问题。最重要的

项目成果

Unraveling the enigma that is neonatal necrotizing enterocolitis.

解开新生儿坏死性小肠结肠炎之谜。

• DOI: 10.1038/jp.2014.155
• 发表时间: 2014
• 期刊: Journal of perinatology : official journal of the California Perinatal Association
• 作者: McElroy,SJ

Innate Immunity in the Small Intestine of the Preterm Infant.

• DOI: 10.1542/neo.12-9-e517
• 发表时间: 2011-09-01
• 期刊: NeoReviews
• 作者: McElroy SJ;Weitkamp JH
• 通讯作者: Weitkamp JH

Normal cerebral, renal and abdominal regional oxygen saturations using near-infrared spectroscopy in preterm infants.

• DOI: 10.1038/jp.2010.71
• 发表时间: 2011-01
• 期刊: JOURNAL OF PERINATOLOGY
• 影响因子: 2.9
• 作者: McNeill, S.;Gatenby, J. C.;McElroy, S.;Engelhardt, B.
• 通讯作者: Engelhardt, B.

Paneth-cell-disruption-induced necrotizing enterocolitis in mice requires live bacteria and occurs independently of TLR4 signaling.

• DOI: 10.1242/dmm.028589
• 发表时间: 2017-06-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: White JR;Gong H;Pope B;Schlievert P;McElroy SJ
• 通讯作者: McElroy SJ