Structure, function, and modulation of claudin cation channels in the GI tract

胃肠道密蛋白阳离子通道的结构、功能和调节

基本信息

批准号：
10675734
负责人：
Fatemeh Khalili-Araghi
金额：
$ 48.82万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675734
关键词：
Address Affect Affinity Amino Acids Biophysics Biopsy CD4 Positive T Lymphocytes Cations Celiac Disease Charge Colitis Computer Models Coupled Defect Development Diarrhea Disease Elements Epithelial Cells Epithelium Family Functional disorder Gastrointestinal tract structure Genetic Glucose Goals Health Human Immune In Vitro Individual Infectious colitis Inflammation Inflammatory Bowel Diseases Interleukin-13 Intestinal Absorption Intestinal Diseases Intestinal Mucosa Intestinal permeability Intestines Ion Channel Ion Transport Ions Knowledge Malabsorption Syndromes Measurement Mediating Membrane Modeling Molecular Monovalent Cations Morbidity - disease rate Mucous Membrane Mus Nutrient Patch-Clamp Techniques Pathway interactions Patients Permeability Pharmacological Treatment Physiological Physiology Process Property Proteins Regulation Research Resolution Role Series Sodium Structure Structure-Activity Relationship T cell therapy Tight Junctions Transmembrane Domain channel blockers design human tissue improved in silico in vivo Model innovation insight intestinal epithelium molecular dynamics monolayer mortality mouse model murine colitis mutant novel novel therapeutic intervention novel therapeutics nutrient absorption patch clamp prevent seal small molecule small molecule inhibitor tool

项目摘要

ABSTRACT Intestinal diseases, including inflammatory bowel disease (IBD), celiac disease, and infectious colitis are associated with epithelial barrier dysfunction that contribute to diarrhea and nutrient malabsorption. Tight junctions seal spaces between epithelial cells and maintain barrier function by controlling paracellular flux. The claudin family of tight junction proteins is critical in defining the tight junction barrier to ions and small molecules. In the gastrointestinal tract, claudin-2 and -15 are particularly important in their role regulating paracellular sodium flux and their altered expression can contribute to intestinal disease development. Using a novel patch clamp technique, we demonstrated that claudin-2 and -15 form gated Na+ selective ion channels in the paracellular space. This is important because it demonstrates that claudins have properties similar to transmembrane ion channels. However, we have limited understanding of how these cation selective claudins contribute to charge and size selective paracellular pores, how these two claudins function singly or together to impact intestinal function, and how they impact disease processes. To address these questions, we built all-atom computer models for claudin-2 and -15 which allowed us to model both claudin structure and pore function. These models also helped us to identify several first-in-class claudin channel blockers that block the pore at low micromolar concentrations. We propose to use these unique and novel computational and small molecule inhibitor tools to investigate how claudin-2 and -15 channels control monovalent cation flux across the tight junction, and how they may differentially regulate cation transport in health and disease. In Aim 1, we will use our claudin-2 and -15 computer models and channel blockers to determine key molecular and structural features that dictate size and charge selectivity. In Aim 2, we will use our existing and new claudin channel blockers to define the individual and combined contributions of claudin-2 and -15 to normal intestinal physiology and disease presentation and development. We will determine the role of claudin-2 and -15 channels in Na+-coupled nutrient co-transport- mediated barrier regulation, mouse models of colitis, and in human IBD. Completion of this line of study is expected to contribute positively to human health by providing key insight into how these channels mediate nutrient absorption, contribute to diarrhea in the setting of colitis, and potentially aid in the development of novel therapies.

抽象的肠道疾病，包括炎症性肠病（IBD），腹腔疾病和感染性结肠炎是与上皮屏障功能障碍有关，导致腹泻和养分吸收不良。紧的连接在上皮细胞之间密封空间，并通过控制细胞细胞通量来保持屏障功能。这克劳丁（Claudin 分子。在胃肠道中，Claudin -2和-15在调节其角色方面尤为重要细胞细胞通量及其表达改变会导致肠道疾病的发展。使用新颖的贴片夹技术，我们证明了claudin -2和-15形式的Na+选择性离子旁细胞空间中的通道。这很重要，因为它证明了克劳丁斯有特性类似于跨膜离子通道。但是，我们对这些阳离子的选择性如何有限 Claudins有助于收费和尺寸选择性细胞细胞毛孔，这两个Claudins如何单独发挥作用或共同影响肠功能，以及它们如何影响疾病过程。为了解决这些问题，我们为Claudin-2和-15构建了全原子计算机模型，使我们能够对Claudin结构和孔建模功能。这些模型还帮助我们确定了几个一流的Claudin通道阻滞剂，以阻止在低微摩尔浓度下孔。我们建议使用这些独特而新颖的计算和小分子抑制剂工具来研究 claudin -2和-15通道如何控制紧密连接的单价阳离子通量，以及它们如何在健康和疾病中差异调节阳离子运输。在AIM 1中，我们将使用Claudin -2和-15 计算机模型和通道阻滞剂，以确定决定大小和结构的关键分子和结构特征充电选择性。在AIM 2中，我们将使用现有和新的Claudin渠道阻滞剂来定义个人以及Claudin -2和-15对正常肠道生理和疾病表现的综合贡献以及发展。我们将确定claudin-2和-15通道在Na+耦合的营养辅助转移中的作用介导的屏障调节，结肠炎的小鼠模型和人类IBD。这项研究的完成是预计通过提供有关这些渠道如何调节的关键见解会对人类健康做出积极贡献营养吸收，在结肠炎的情况下导致腹泻，并有助于发展新疗法。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular dynamics analyses of CLDN15 pore size and charge selectivity.

CLDN15 孔径和电荷选择性的分子动力学分析。

DOI：
10.1101/2023.08.16.553400
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
McGuinness,Sarah;Li,Pan;Li,Ye;Fuladi,Shadi;Konar,Sukanya;Sajjadi,Samaneh;Sidahmed,Mohammed;Li,Yueying;Shen,Le;Araghi,FatemehKhalili;Weber,ChristopherR
通讯作者：
Weber,ChristopherR