Regulation of Inflammation in Immature Intestine

描述（由申请人提供）：候选人：克劳德博士开始她的研究期间，她的泌尿学奖学金。在Michael S博士的指导下，卡普兰，她研究了血小板活化因子对离子转运的影响。毕业后，她加入了波士顿儿童医院（TCH）的新生儿医学部和马萨诸塞州总医院（MGH）的W。艾伦步行者。她寻求发展信号转导方面的专业知识，以研究肠道炎症调节的发展，因为它与坏死性小肠结肠炎（NEC）的发病机制有关。她致力于成为一名物理学家兼科学家。环境：候选人将在信号转导，胃肠道免疫学和细胞生物学专家的密切监督下工作。步行者博士和鲍比·切拉伊尔博士将担任导师。TCH MGH和哈佛医学院致力于提供一个培育科学环境。这包括实验室空间，接触高级科学家，以及她发展成为独立调查员所需的培训。医学部致力于提供受保护的研究时间。研究：证据表明，肠上皮-微生物相互作用是发育调节的。初步数据表明，与成人肠上皮细胞（IEC）相比，人胎儿IEC在响应外源性（革兰氏阴性菌，鞭毛蛋白）和内源性（肿瘤坏死因子α，白细胞介素1 β）炎症介质时产生的白细胞介素8（IL-8）过多。本项目的目的是在细胞和分子水平上描述肠道炎症在未成熟肠道中的调节机制。本申请的假设是未成熟肠上皮中改变的受体表达和/或信号转导途径导致对微生物和炎症介质相互作用的过度炎症反应。该应用程序旨在1.阐明未成熟肠道中刺激IL-8分泌增加背后的机制，以及2.测试这些发现的体内相关性。实验设计利用细胞和器官培养模型、NEC大鼠模型和人NEC肠样品。这些研究应该开始回答关键的问题-“是什么导致了NEC炎症状态的开始和持续？"

DESCRIPTION (provided by applicant): The Candidate: Dr. Claud began her research during her neonatology fellowship. Under the mentorship of Dr. Michael S. Caplan, she investigated the effect of platelet activating factor on ion transport. After her fellowship she joined the division of Newborn Medicine at The Children's Hospital (TCH), Boston and the Massachusetts General Hospital (MGH) laboratory of Dr. W. Allan Walker. She seeks to develop expertise in signal transduction in order to study the development of intestinal inflammatory regulation as it relates to the pathogenesis of necrotizing enterocolitis (NEC). She is committed to a career as a physician-scientist. The Environment: The candidate will work under the close supervision of experts in signal transduction, gastrointestinal immunology, and cell biology. Dr. Walker and Dr. Bobby Cherayil will serve as mentors. TCH MGH and Harvard Medical School are committed to providing a nurturing scientific environment. This includes laboratory space, access to senior scientists, and the training necessary for her development into an independent investigator. The neonatology division is committed to providing protected research time. The Research: Evidence suggests that intestinal epithelial-microbial interactions are developmentally regulated. Preliminary data demonstrate that compared to adult intestinal epithelial cells (IEC), human fetal IEC have an exaggerated production of interleukin 8 (IL-8) in response to exogenous (gram-negative bacteria, flagellin) and endogenous (tumor necrosis factor alpha, interleukin 1 beta) inflammatory mediators. The objective of this project is to delineate the mechanisms by which intestinal inflammation is regulated in the immature intestine at the cellular and molecular level. The hypothesis for this application is that altered receptor expression and/or signal transduction pathways in immature intestinal epithelium lead to an exaggerated inflammatory response to microbial and inflammatory mediator interaction. This application is designed to 1. Elucidate the mechanism behind increased stimulated IL-8 secretion in the immature intestine, and 2. Test the in vivo relevance of these findings. The experimental design utilizes cell and organ culture models, a rat model of NEC, and human NEC intestinal samples. These studies should begin to answer the critical question- "What is responsible for the initiation and perpetuation of the inflammatory state in NEC?"