Role of Paneth Cells in Development of Necrotizing Enterocolitis

潘氏细胞在坏死性小肠结肠炎发展中的作用

• 批准号: 8581538
• 负责人: Steven James McElroy
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581538
• 关键词: Ablation; Address; Affect; Age; Animal Model; Animals; Bacteria; Cell secretion; Cells; Cytoplasmic Granules; Data; Development; Disease; Disease model; Epithelial; Epithelium; Functional disorder; Funding; Goals; Health; Human; Human body; Immune; Immune system; Infant; Inflammation; Inflammation Mediators; Injury; Intestines; Klebsiella; Klebsiella Infections; Knowledge; Lead; Methods; Mission; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Nature; Necrosis; Necrotizing Enterocolitis; Neonatal; Newborn Infant; Paneth Cells; Pathogenesis; Pathology; Penetration; Play; Positioning Attribute; Pregnancy; Premature Infant; Premature Infant Diseases; Public Health; Publishing; Research; Rodent; Role; Signal Pathway; Signal Transduction; Small Intestines; Staging; System; TLR4 gene; Testing; Tissues; United States; antimicrobial; antimicrobial peptide; base; clinical application; cost; disability; gastrointestinal; ileum; immune function; innovation; interest; intestinal crypt; mortality; mouse model; novel; novel therapeutics; pre-clinical; prevent; public health relevance; response

DESCRIPTION (provided by applicant): Neonatal necrotizing enterocolitis (NEC) is the single most devastating gastrointestinal cause of mortality and morbidity in premature infants. Although the pathophysiology of NEC is uncertain, the leading hypothesis is that intestinal bacteria penetrate the immature intestinal epithelial barrier defenses, leading to tissue invasion and subsequent necrosis. A key gastrointestinal cell of the innate immune system is the Paneth cell, which is located in the base of the intestinal crypts. Paneth cells protect the intestine through secretion of pro-inflammatory mediators and antimicrobial substances. Compared to age-matched controls, infants with NEC have significantly decreased numbers of Paneth cells. Despite the key role Paneth cells play in immune function, it is unclear what role these cells play in the pathogenesis of NEC. Traditional animal models have not yet developed Paneth cells, and are thus unable to address this gap in knowledge. The overall objective of this pre-clinical application is to determine the role of Paneth cells in the development of tissue injury in the immature intestine. To achieve this objective, we will utilize our newly described mouse model of NEC that uses Paneth cell necrosis to induce NEC-like injury. Our hypothesis is that Paneth cell loss renders the immature small intestine susceptible to development of NEC. In this application, we propose to test this hypothesis in the following two Aims: 1: Establish the mechanism of Paneth cell involvement in the pathogenesis of NEC. Infants with NEC lack Paneth cells, and Paneth cell ablation in the presence of Klebsiella produces NEC- like pathology in mice. However, the role of Paneth cells in intestinal injury remains unclear. In this Aim we will examine methods of Paneth cell loss, and the role of Paneth cell secretions to establish how Paneth cell disruption renders the immature ileum susceptible to injury. 2: Establish the role of TLR4 signaling in Paneth cell ablation-induced NEC. Bacteria are required for development of NEC, and TLR4 activation has been proposed as an initiator for disease development4. In the ileum where NEC occurs, TLR4 is expressed in the intestinal crypts. However, these studies were done in intestines that had not yet developed Paneth cells. Thus, it is unclear what role TLR4 plays in Paneth cell ablation-induced NEC. In this Aim we will examine the TLR4 signaling pathway in connection to Paneth cell disruption and subsequent injury. These proposed studies are innovative as they investigate a heretofore-unappreciated role for Paneth cells in the development of NEC. The results of this research will provide a clearer understanding of the mechanism of Paneth cell ablation-induced NEC in the immature intestine. This is the first important step needed for developing novel ways to predict disease development and new pharmacologic strategies to treat NEC.

描述（由申请人提供）：新生儿坏死性小肠结肠炎（NEC）是早产儿死亡和发病的单一最具破坏性的胃肠道原因。虽然NEC的病理生理学尚不确定，但主要假设是肠道细菌穿透未成熟的肠上皮屏障防御，导致组织侵袭和随后的坏死。先天免疫系统的关键胃肠细胞是潘氏细胞，其位于肠隐窝的基部。潘氏细胞通过分泌促炎介质和抗菌物质来保护肠道。与年龄匹配的对照组相比，NEC婴儿的潘氏细胞数量显著减少。尽管潘氏细胞在免疫功能中起着关键作用，但尚不清楚这些细胞发挥的作用 NEC的发病机制。传统的动物模型尚未开发出潘氏细胞，因此无法解决这一知识空白。该临床前应用的总体目标是确定潘氏细胞在未成熟肠组织损伤发展中的作用。为了实现这一目标，我们将利用我们新描述的NEC小鼠模型，该模型使用潘氏细胞坏死来诱导NEC样损伤。我们的假设是，潘氏细胞的损失，使未成熟的小肠容易发展NEC。在本申请中，我们提出在以下两个目标中检验该假设：1：建立潘氏细胞参与NEC发病机制的机制。 患有NEC的婴儿缺乏潘氏细胞，并且在克雷伯氏菌存在的情况下潘氏细胞消融在小鼠中产生NEC样病理。然而，潘氏细胞在肠损伤中的作用仍不清楚。在这个目标中，我们将检查潘氏细胞损失的方法，以及潘氏细胞分泌物的作用，以确定潘氏细胞破裂如何使未成熟回肠对损伤敏感。2：确定TLR4信号传导在潘氏细胞消融诱导的NEC中的作用。 细菌是NEC发展所必需的，TLR4激活已被提议为疾病发展的启动子4。在发生NEC的回肠中，TLR4在肠隐窝中表达。然而，这些研究是在尚未发育潘氏细胞的肠道中进行的。因此，目前还不清楚TLR4在潘氏细胞消融诱导的NEC中起什么作用。在这个目标中，我们将研究TLR4信号通路与潘氏细胞破坏和随后的损伤。这些拟议的研究是创新的，因为他们调查了潘氏细胞在NEC发展中迄今未被重视的作用。本研究的结果将为进一步了解潘氏细胞消融诱导未成熟小肠NEC的机制提供依据。这是开发预测疾病发展的新方法和治疗NEC的新药理学策略所需的第一个重要步骤。