Regulatory role for an epithelial repair protein, LINGO2, in colitis

上皮修复蛋白 LINGO2 在结肠炎中的调节作用

基本信息

批准号：
10039666
负责人：
Nicole Maloney Belle
金额：
$ 16.84万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10039666
关键词：
3-Dimensional Abscess Affect Azoxymethane Biological Models Biology Bone Marrow CRISPR/Cas technology Carcinogens Carcinoma Cells Cellular biology Chimera organism Chronic Colitis Colitis associated colorectal cancer Colonic Neoplasms Data Defect Development Disease Disease model EGFR inhibition Environment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Epithelial Cells Epithelium Exposure to Faculty Fistula Foundations Functional disorder Funding Genes Genetic Genetic Polymorphism Goals Growth Hematopoietic Hemorrhagic colitis Homeostasis Human IL6 gene Immune Immunology In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-6 Intestines Investigation Kinetics Knock-in Knock-out Knockout Mice Leucine-Rich Repeat Malignant - descriptor Malignant Neoplasms Modeling Molecular Mucous Membrane Mus Mutant Strains Mice Myelogenous Myeloid Cells Organoids Pathway interactions Patients Pennsylvania Phosphorylation Predictive Factor Predisposition Production Protein Family Proteins Publications Publishing RIPK1 gene Regulation Relapse Research Risk Role STAT3 gene Severities Signal Transduction Sodium Dextran Sulfate Susceptibility Gene Techniques Testing Training Transplantation United States National Institutes of Health Universities Up-Regulation adenoma career development colitis associated cancer cytokine dextran sulfate sodium induced colitis experimental study genetic manipulation genome wide association study inflammatory disease of the intestine innovation intestinal barrier intestinal epithelium knowledge base leucine-rich repeat protein member microbiota mouse model novel overexpression receptor repaired response skills small molecule tenure track tool trefoil factor tumor tumor microenvironment tumorigenic

项目摘要

PROJECT SUMMARY Inflammatory bowel disease (IBD) constitutes a spectrum of incurable, relapsing and remitting disorders driven by intestinal mucosal barrier function defects and aberrant pro-inflammatory responses directed against microbial flora. IBD patients are at increased risk of developing colitis-associated colorectal cancer (CAC) but the epithelial specific mechanisms that control it are incompletely understood. Also unclear are the genetic factors that predict which IBD patients are likely to progress to CAC. The research focus of this proposal is to uncover how dysregulation of a novel epithelial repair protein, Leucine rich repeat and Ig domain-containing, nogo receptor-interacting protein family 2 (LINGO2) contributes to malignant transformation. In preliminary data, we show that Lingo2 deficiency in epithelial cells results in up-regulation of EGFR phosphorylation, prolonged STAT3 activation in response to IL6 treatment and increased proliferation compared to wildtype cells. Furthermore, Lingo2 deficient mice have severe dextran sodium sulfate (DSS) induced colitis that is rescued by EGFR inhibition. We demonstrate that Lingo2 is expressed in immune cells and its loss in the hematopoietic compartment contributes to susceptibility to colitis. Consistent with the published observations that increased EGFR signaling is pro-tumorigenic, we show that when exposed to azoxymethane (AOM) and DSS, Lingo2 deficient mice are more susceptible to the development of CAC compared to control mice. I therefore hypothesize that Lingo2 protects against the development of CAC through regulation of EGFR and STAT3 activity. The objective is to first mechanistically dissect the cell autonomous role of Lingo2 in epithelial cells in protection from CAC and then to understand whether Lingo2 deficiency in the microenvironment is important for CAC. My hypothesis will be tested through two inter-related Specific Aims that will examine the interplay of LINGO2 and EGFR signaling in epithelial cells in CAC (Aim 1) and then evaluate how Lingo2 deficiency affects the production of STAT3 activating cytokines and activity of myeloid cells in CAC (Aim 2). The experiments proposed will use various innovative approaches including the use of unique knock-in murine models, 3D organoid culture model systems and organoid orthotopic transplantation. The proposed research is significant because it will provide new information about a novel tumor suppressive molecular pathway. University of Pennsylvania provides the perfect research environment to conduct this investigation given local expertise in the inter-related fields of mucosal biology, epithelial biology and immunology. The candidate will gain fundamental skills in murine and in vitro disease modeling and broaden her immunology and epithelial biology knowledge base. These skill sets will greatly enhance the candidate's career development into an independent NIH funded tenure-track faculty member with the long term goal of understanding the mechanisms that control mucosal repair and homeostasis.

项目摘要炎症性肠病（IBD）构成了一系列无法治愈的，复发和恢复疾病驱动的通过肠粘膜屏障功能缺陷和针对针对的异常促炎反应微生物菌群。 IBD患者患有结肠炎相关的结直肠癌（CAC）的风险增加，但无法完全理解控制它的上皮特定机制。遗传也不清楚预测哪些IBD患者可能会发展为CAC的因素。该提议的研究重点是发现新型上皮修复蛋白的失调，富含亮氨酸的重复和Ig结构域的失调， Nogo受体相互作用蛋白家族2（Lingo2）有助于恶性转化。在初步数据，我们显示上皮细胞中的Lingo2缺乏导致EGFR磷酸化的上调，与野生型相比细胞。此外，Lingo2缺乏小鼠具有严重的葡萄糖硫酸钠（DSS）诱导的结肠炎 EGFR抑制作用。我们证明了Lingo2在免疫细胞中表达，其损失在造血室有助于对结肠炎的敏感性。与已发表的观察一致 EGFR信号的增加是促肿瘤的，我们表明，当暴露于甲氧基甲烷（AOM）和与对照小鼠相比，DSS，Lingo 2缺乏小鼠更容易受到CAC的发展。我因此，假设Lingo2通过调节EGFR和 STAT3活动。目的是首先机械地剖析Lingo2在上皮中的细胞自主作用保护侵害CAC的细胞，然后了解微环境中的Lingo2缺乏症是否是对于CAC很重要。我的假设将通过两个相互关联的特定目的来检验 CAC中上皮细胞中Lingo2和EGFR信号传导的相互作用（AIM 1），然后评估Lingo2如何缺乏影响CAC中STAT3激活细胞因子和髓样细胞活性的产生（AIM 2）。提出的实验将使用各种创新方法，包括使用独特的敲门鼠模型，3D类器官培养模型系统和器官矫形器移植。拟议的研究是重要的是因为它将提供有关新型肿瘤抑制分子途径的新信息。宾夕法尼亚大学提供了一个完美的研究环境，以进行本地调查粘膜生物学，上皮生物学和免疫学的相关领域的专业知识。候选人会在鼠和体外疾病建模中获得基本技能，并扩大其免疫学和上皮生物学知识基础。这些技能将大大改善候选人的职业发展独立NIH资助了终身教师，其长期目标是理解控制粘膜修复和稳态的机制。