HB-EGF Therapy for Necrotizing Entercolitis

HB-EGF 治疗坏死性小肠结肠炎

基本信息

批准号：
8074971
负责人：
GAIL E BESNER
金额：
$ 28.35万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074971
关键词：
Actins Acute Adhesions Affect Anti-Inflammatory Agents Bacterial Translocation Biological Preservation Cause of Death Cells Chemicals Clinical Clinical Protocols Complex DTR gene Development Dextrans Disease E-Cadherin Electrical Resistance Enteral Epithelial Cells Evaluation Exposure to Family Feeds Fiber Focal Adhesions Gastrointestinal Diseases Goals Hemorrhagic Shock Histologic Histology Hour Human Hypoxia Immunohistochemistry In Vitro Infiltration Injury Integrins Intestinal Mucosa Intestines Ischemic Bowel Disease Knock-out Knockout Mice Label Lead Lesion Measures Mediator of activation protein Modeling Molecular Morbidity - disease rate Mucous Membrane Mus Myosin ATPase Necrotizing Enterocolitis Neonatal Newborn Infant Nitrogen PTK2 gene Permeability Predisposition Premature Infant Process Production Proteins Public Health Pulmonary Valve Insufficiency Rattus Regimen Reperfusion Injury Research Research Personnel Resistance Resuscitation Reverse Transcriptase Polymerase Chain Reaction Role Small Interfering RNA Specimen Testing Therapeutic Time Tissues Transgenic Mice Transgenic Organisms Western Blotting Work Wound Healing absorption base dextran feeding fluorescein isothiocyanate dextran free radical oxygen gain of function heparin-binding EGF-like growth factor in vivo inhibitor/antagonist injured loss of function mRNA Expression macrophage member migration mortality mouse model natural hypothermia neonate neutrophil novel strategies paxillin prevent programs pup receptor rho

项目摘要

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of newborns, and is anticipated to replace pulmonary insufficiency as the leading cause of death in premature babies. We have accumulated multiple lines of evidence supporting a role for heparin-binding EGF-like growth factor (HB-EGF) in protection of the intestines from injury via preservation of the intestinal mucosa. The long term goal of our work is based on the premise that protection of the intestinal mucosa from injury represents a logical target for the development of novel strategies to prevent the disease, and involves the clinical administration of HB- EGF, both therapeutically and prophylactically, to protect neonates from NEC. Recently, we have shown that HB-EGF decreases histologic injury and mortality in a rat model of NEC whereby rat pups are exposed to repeated cycles of hypoxia/hypothermia, hypertonic feedings and exposure to LPS (HHHTF+LPS), leading to intestinal lesions indistinguishable from those of human NEC. Our central hypothesis is that tissues afflicted with NEC have a local deficiency of HB-EGF which leaves a portion of the intestine susceptible to injury, and that administration of exogenous HB-EGF protects the intestine from injury via promotion of intestinal restitution, thereby preserving intestinal permeability. Towards our goal, we have proposed three specific aims that will allow a better understanding of the mechanistic basis of HB-EGF function in injured intestine, as a prerequisite to developing therapeutic clinical protocols: Aim [1] To test the hypothesis that HB-EGF gain-of-function will lead to resistance to NEC whereas HB-EGF loss-of-function will lead to increased susceptibility to NEC. We will subject neonatal HB-EGF transgenic and knockout mice to experimental NEC by exposing them to HHHTF, with evaluation of gut barrier function by systemic absorption of enteral FICT- dextran, Ussing chamber ex vivo studies and determination of bacterial translocation; intestinal histology; and mortality. Aim [2] To test the hypothesis that HB-EGF protects the intestine in vivo by inducing mediators of intestinal restitution during HHHTF-induced NEC. The mouse model of NEC will be used in HB- EGF TG, HB-EGF KO and WT mice, with measured endpoints including mRNA expression and protein production of mediators of restitution (integrins, FAK, paxillin, Rho). Ex vivo Ussing chamber studies will also be performed to further examine the mechanisms by which HB-EGF promotes intestinal restitution. Aim [3] To test the hypothesis that HB-EGF promotes restitution by affecting epithelial cell-matrix interactions. The in vitro scrape-wounding model of restitution will be utilized to examine the molecular mechanisms utilized by HB-EGF to promote restitution. The relevance of this research to public health is that it will provide a better understanding of the mechanisms utilized by HB-EGF in protection of the intestines from NEC, as a prerequisite for the development of HB-EGF-based therapeutic regimens.

描述（由申请人提供）：坏死性小肠结肠炎（NEC）是最常见的新生儿胃肠道疾病，预计将取代肺部不足，因为早产婴儿的主要死亡原因。我们积累了多种证据，这些证据支持肝素结合EGF样生长因子（HB-EGF）在保护肠道免受肠道损伤的保护中的作用。我们工作的长期目标是基于这样的前提：保护肠粘膜免受伤害是制定新型策略以防止疾病的逻辑目标，并涉及治疗和预防性在治疗和预防性上的临床给药，以保护新生儿免受NEC的侵害。最近，我们已经表明，HB-EGF在NEC的大鼠模型中降低了组织学损伤和死亡率，从而将大鼠幼崽暴露于低氧/低温，低渗透喂养，高渗喂养以及LPS（HHHTF+LPS）（HHHTF+LPS）的重复循环中，导致与人类NEC的肠道不可分割的肠道病变。我们的中心假设是，患有NEC的组织具有HB-EGF的局部缺陷，这使一部分肠道易于受伤，并且外源性HB-EGF的给药可通过促进肠道恢复，从而保护肠道，从而保护肠道，从而保护肠道渗透性。 Towards our goal, we have proposed three specific aims that will allow a better understanding of the mechanistic basis of HB-EGF function in injured intestine, as a prerequisite to developing therapeutic clinical protocols: Aim [1] To test the hypothesis that HB-EGF gain-of-function will lead to resistance to NEC whereas HB-EGF loss-of-function will lead to increased susceptibility to NEC.我们将通过将它们暴露于HHHTF的情况下，使新生儿HB-EGF转基因和基因敲除小鼠通过全身吸收肠道脱氧于HHTF，通过对肠道屏障的功能进行评估，并使用了室内室外研究并确定细菌易位；肠组织学；和死亡率。 AIM [2]测试HB-EGF通过在HHHTF诱导的NEC期间诱导肠道恢复的介体来保护肠道的假设。 NEC的小鼠模型将用于HB- EGF TG，HB-EGF KO和WT小鼠，并具有测量的终点，包括mRNA表达和蛋白质的蛋白质产生恢复原状的介体（整合素，FAK，Paxillin，Rho）。还将进行外体研究，以进一步研究HB-EGF促进肠道恢复原状的机制。 AIM [3]测试HB-EGF通过影响上皮细胞 - 基质相互作用来促进恢复原状的假设。将利用体外刮擦的恢复模型来检查HB-EGF使用的分子机制来促进恢复原状。这项研究与公共卫生的相关性是，它将更好地理解HB-EGF在保护肠子免受NEC中使用的机制，这是开发基于HB-EGF的治疗方案的先决条件。