Claudin expression regulates mucus function

Claudin 表达调节粘液功能

• 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
• 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' 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

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 项目总结： 炎症性肠病(IBD)，包括克罗恩病(CD)和 溃疡性结肠炎(UC)，涉及反复免疫激活和进行性降解 肠道内层。IBDS是一种特发性疾病，目前的治疗方法往往不能 改善炎症症状，促进疾病进展。糟糕的结果 可能是由于IBD发病机制的复杂性，这涉及到遗传和 环境因素如高脂肪、低纤维的西式饮食。因此，至关重要的是 新的治疗策略在遗传易感性方面显示出疗效 IBD。这项建议旨在探索基因相关性IBD的一种新假说 发病机制，并评估一种潜在饮食疗法在基因敲除中的疗效 IBD小鼠模型。重要的是，肠道的细胞和/或粘液屏障的丧失 所有人类IBD的共同病因特征；包括粘液稠度的变化 和Claudin蛋白的表达。我们的初步数据表明，一种新的功能 基于克拉丁的屏障与粘液屏障的关系。因此，这 该提案将解决以下假设：炎性细胞因子破坏离子/液体 通过异常的claudin表达在结肠内保持动态平衡，导致 粘液屏障减弱，对疾病的易感性增加。目标一号将直接 验证这样的假设：在炎症期间，Claudin蛋白起到减少粘液的作用 密度和粘液形成有效屏障的能力。虽然我们的初步数据 强烈支持这一假设，目前尚不清楚治疗是否可以改变跛行 表情。事实上，对claudin的功能和调控知之甚少。然而， 高纤维/可发酵纤维饮食已在小鼠中被证明支持粘液性 细菌在结肠中，从而增加粘液密度和保护功能。威尔饮食 事实证明，支持粘液屏障的药物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的增加 对肝细胞核因子α-IBD小鼠模型有治疗作用 (HNF4)基因敲除小鼠。HNF4突变在UC和CD中发现，已被证明是 引起claudin基因表达的变化，并在肠道中清除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 确定膳食纤维是否会缓解或加剧下列小鼠的结肠炎症状 遗传性易患慢性结肠炎。