Claudin expression regulates mucus function

Claudin 表达调节粘液功能

基本信息

批准号：
10515281
负责人：
Christopher Todd Capaldo
金额：
$ 40.59万
依托单位：
HAWAII PACIFIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-26 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515281
关键词：
16S ribosomal RNA sequencing Address Affect American Antigens Bacteria Binding Biological Assay CRISPR/Cas technology Cell Count Cell Culture System Cell Culture Techniques Cell Line Cells Chronic Colitis Colon Complex Crohn&apos s disease Cryoultramicrotomy Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Diet Diet Modification Diet therapy Dietary Fiber Disease Disease Progression Environmental Risk Factor Epithelial Epithelial Cells Etiology Excision Fatty acid glycerol esters Fiber Fluid Balance Gene Expression Genes Genetic Genetic Predisposition to Disease Goblet Cells HNF4A gene HT29 Cells Histology Human In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interferons Intestines Ions Knockout Mice Leaky Gut Link LoxP-flanked allele Lung Mediating Messenger RNA Methylcellulose Molecular Abnormality Monitor Morphology Mucous Membrane Mucous body substance Mus Mutation Osmotic Pressure Outcome Pathogenesis Pathologic Pathology Patients Penetration Permeability Play Population Predisposition Property Protein Family Proteins Regulation Research Role Spontaneous colitis Structure Symptoms TNF gene Testing Therapeutic Tight Junctions Ulcerative Colitis base care costs colonic crypt conditional knockout cytokine density efficacy evaluation experimental study hepatocyte nuclear factor immune activation in vivo indexing loss of function member microbial monolayer mouse model mucosal microbiota murine colitis novel novel therapeutic intervention overexpression pathogen prevent protein expression protein function seal small molecule stem cells targeted treatment transcription factor water flow western diet

项目摘要

PAR-21-155 Capaldo Project Summary: Inflammatory Bowel Diseases (IBDs), encompassing both Crohn’s Disease (CD) and Ulcerative Colitis (UC), involve recurring immune activation and progressive degradation of the intestinal lining. IBDs are idiopathic diseases and current therapies frequently fail to ameliorate inflammatory symptoms, contributing to disease progression. Poor outcomes may be due to the complexities of IBD pathogenesis, which involve both genetic and environmental factors such as a high fat, low fiber western diet. Therefore, it is vital that new therapeutic strategies demonstrate efficacy in the context of genetic predisposition to IBD. This proposal aims to explore both a novel hypothesis for gene-related IBD pathogenesis, and evaluate the efficacy of a potential dietary therapy in a knockout mouse model of IBD. Importantly, loss of the cellular and/or mucus barriers of the gut is a common etiological feature of all human IBDs; including changes in mucus consistency and claudin protein expression. Our preliminary data suggest a novel functional relationship between the claudin-based barrier and the mucus barrier. Therefore, this proposal will address the following hypothesis: Inflammatory cytokines disrupt ion/fluid homeostasis in the colon through aberrant claudin expression, resulting in a weakened mucus barrier and increased susceptibility to disease. Aim 1 will directly test the hypothesis that, during inflammation, claudin proteins function to reduce mucus density and the ability of mucus to form an effective barrier. While our preliminary data strongly support this hypothesis, it is unclear if therapies can be directed at altering claudin expression. Indeed, claudin function and regulation is very poorly understood. However, high fiber/fermentable fiber diets have been demonstrated in mice to support mucophilic bacteria in the colon, thereby increasing mucus density and protective function. Will diets that support the mucus barrier prove effective in patients bearing genetic deficiencies that weaken the cellular barrier? In Aim 2 we will determine if an increase in mucus density has therapeutic benefit in a mouse model of IBD, Hepatocyte Nuclear Factor alpha (HNF4) knockout mice. HNF4 mutations are found in UC and CD, have been shown to cause changes in claudin gene expression, and removal of Hnf4a in the intestine is sufficient to cause colitis in mice. We will assess mucus function in these mice in vivo, and determine if dietary fiber will alleviate or exacerbate colitis symptoms in mice that are genetically predisposed to chronic colitis development.

PAR-21-155 卡帕尔多项目概要：炎症性肠病 (IBD)，包括克罗恩病 (CD) 和溃疡性结肠炎（UC）涉及反复的免疫激活和进行性退化 IBD 是一种特发性疾病，目前的治疗方法常常无法治愈。改善炎症症状，导致疾病进展。可能是由于 IBD 发病机制的复杂性，涉及遗传和环境因素，例如高脂肪、低纤维的西方饮食，因此至关重要。新的治疗策略在遗传易感性背景下证明了疗效该提案旨在探索基因相关 IBD 的新假设。发病机制，并评估潜在饮食疗法在基因敲除中的功效重要的是，肠道细胞和/或粘液屏障的丧失是 IBD 的小鼠模型。所有人类 IBD 的共同病因学特征；包括粘液稠度的变化我们的初步数据表明了一种新的功能。因此，密蛋白屏障和粘液屏障之间的关系。该提案将解决以下假设：炎症细胞因子破坏离子/液体通过异常的紧密蛋白表达来维持结肠的稳态，从而导致粘液屏障减弱和对疾病的易感性增加将直接增加。检验以下假设：在炎症过程中，密蛋白具有减少粘液的功能密度和粘液形成有效屏障的能力，而我们的初步数据。强烈支持这一假设，目前尚不清楚治疗是否可以针对改变紧密蛋白事实上，人们对密蛋白的功能和调节知之甚少。高纤维/可发酵纤维饮食已在小鼠中被证明可以支持粘液质结肠中的细菌，从而增加粘液密度和保护功能。事实证明，支持粘液的屏障对患有遗传缺陷的患者有效削弱细胞屏障？在目标 2 中，我们将确定粘液密度是否增加对 IBD（肝细胞核因子 α）小鼠模型具有治疗效果 (HNF4α) 敲除小鼠在 UC 和 CD 中发现了 HNF4α 突变。导致claudin基因表达的变化，并且去除肠道中的Hnf4a 足以引起小鼠结肠炎，我们将在体内评估这些小鼠的粘液功能，并且确定膳食纤维是否会减轻或加重小鼠的结肠炎症状具有慢性结肠炎发展的遗传倾向。