Paneth Cell Cryptdins in Innate Intestinal Host Defense

潘氏细胞隐蛋白在先天肠道宿主防御中的作用

• 批准号: 6685409
• 负责人: PATRICIA LANEE WEI DENNING
• 金额: $ 12.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-20 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6685409
• 关键词: I kappa B beta; calcium flux; cell line; chloride ion; defensins; interleukin 8; intestinal mucosa; membrane channels; mucosal immunity; nuclear factor kappa beta; recombinant proteins; secretion; I kappa B beta; calcium flux; cell line; chloride ion; defensins; interleukin 8; intestinal mucosa; membrane channels; mucosal immunity; nuclear factor kappa beta; recombinant proteins; secretion

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the role of Paneth cell cryptdins in innate intestinal host defense. Disregulation of intestinal host defense mechanisms likely plays an important role in the pathophysiology of inflammatory bowel disease (IBD) and necrotizing eneterocolitis (NEC). Paneth cells, located at the base of intestinal crypts produce intestinal-specific alpha-defensins, termed cryptdins, which exhibit potent antimicrobial properties. We propose that Paneth cell cryptdins contribute to intestinal host defense by acting both as antimicrobial peptides and as paracrine pore-forming peptides to induce epithelial CI-secretory and IL-8 mediated proinflammatory responses. The specific aims of this project are to: (i) define the mechanism of intestinal epithelial CI- secretion induced by Paneth cell secretions and granule contents (ii) explain how Paneth cell cryptdins induce a proinflammatory response from intestinal epithelial cells and (iii) examine the bioactivity of the human Paneth cell alpha-defensin HD-5. Studies proposed will utilize native murine cryptdins as Paneth cell secretions, synthesized and folded murine cryptdins, and recombinant human alpha-defensins. We will model cryptdin-epithelial interactions using the human intestinal cell line T84 and examine the mechanisms of cryptdin-induced CI- and IL-8 secretion. These studies will elucidate the role of cryptdins in intestinal host defense and innate immunity, and contribute to our understanding of the pathophysiology of many intestinal inflammatory disorders. The candidate's long-term career goal is to develop an academic career in neonatology with a basic research focus on gastrointestinal host defense mechanisms. {The rich environment provided by the support of her mentor, Dr. Andrew Neish, M.D. (Associate Professor in Pathology and Laboratory Medicine, Emory University Medical School), her co-mentor, Dr. Wayne Lencer, M.D. (Associate Professor in Pediatrics, Harvard Medical School), her advisory committee (Dr. Andre Ouellette, Ph.D., Professor in Pathology, University of California School of Medicine, Irvine, Dr. Sean Colgan, Ph.D., Associate Professor in Anesthesia, Harvard Medical School, and Dr. Charles Parkos, M.D., Ph.D., Associate Professor in Pathology and Laboratory Medicine, Emory University Medical School), her collaborators, and Emory University School of Medicine will provide the resources necessary to help her achieve her objectives.

描述（由申请人提供）： 该提议的目的是阐明泛池牢房在先天肠道宿主防御中的作用。肠道宿主防御机制的疏离可能在炎症性肠病（IBD）和坏死性结肠炎（NEC）的病理生理学中起重要作用。 Paneth细胞位于肠道隐窝的底部，产生肠道特异性α-防御素，称为隐脚蛋白，它们具有有效的抗菌特性。我们提出，Paneth细胞隐脚蛋白通过用作抗菌肽和旁分泌孔形成的肽来诱导上皮CI分泌和IL-8介导的促炎反应，从而有助于肠道宿主防御。该项目的具体目的是：（i）定义Paneth细胞分泌和颗粒含量引起的肠上皮Ci-分泌的机制（II）解释了Paneth Celleth Cryptdins如何诱导肠道上皮细胞和（III）的促炎反应检查人类Paneth Cell Ellpha-Paneth Elpha-phapha-defefeSensin-defefensinsin-hd-5。提出的研究将利用本地鼠隐脚蛋白作为泛细胞分泌物，合成和折叠的鼠隐脚蛋白以及重组人α-防御素。我们将使用人肠细胞系T84对隐脚蛋白上皮相互作用进行建模，并检查加密蛋白诱导的CI-8和IL-8分泌的机制。这些研究将阐明隐脂蛋白在肠道宿主防御和先天免疫中的作用，并有助于我们理解许多肠道炎症性疾病的病理生理学。候选人的长期职业目标是发展新生儿学的学术职业，基础研究重点是胃肠道宿主防御机制。 {由她的导师Andrew Neish博士（埃默里大学医学院病理学和实验室医学副教授）提供的丰富环境，她的同事，M.D。Wayne Lencer博士（哈佛大学医学院儿科学副教授），她的顾问委员会，她的顾问委员会（她的顾问委员会）博士学位，哈佛医学院麻醉副教授和医学博士的Charles Parkos博士，埃默里大学医学院病理学和实验室医学副教授），她的合作者和埃默里大学医学院将提供必要的资源来帮助她实现自己的目标。