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Contributions of the enterocyte brush border to intestinal health and disease

肠上皮细胞刷状缘对肠道健康和疾病的贡献

基本信息

批准号：
10651348
负责人：
Kelli Lynn VanDussen
金额：
$ 48.16万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651348
关键词：
Acute Address Adherent Culture Affect Aftercare Agonist Air Anti-Inflammatory Agents Apical Area Binding Biological Biological Markers Biopsy Biopsy Specimen Body Weight decreased Brush Border Cell Culture Techniques Cell physiology Clinical Colitis Colon Colon Injury Crohn&apos s disease Crossbreeding Data Defect Development Diarrhea Digestion Disease Distal Distant Duodenum Dyslipidemias Enterocytes Environment Environmental Risk Factor Enzymes Epithelial Cells Epithelium Fatty acid glycerol esters Future Goals Health Hepatocyte High Fat Diet Histologic Homeostasis Host Defense Human Ileal Diseases In Vitro Individual Inflammation Inflammatory Injury Intestinal Diseases Intestines Knowledge Length Ligands Link Lipids Liquid substance Mediating Membrane Metabolic Methods Modeling Molecular Morphology Mouse Strains Mucin 1 protein Mucous Membrane Mus Nuclear Receptors Outcome PPAR alpha Pathologic Pathology Pathway Analysis Pathway interactions Patients Peroxisome Proliferators Phenotype Physiological Physiology Pilot Projects Poly I-C Prediction of Response to Therapy Property Refractory Disease Regulation Reporting Risk Role Signal Transduction Site Small Intestines Sodium Dextran Sulfate Structure Surface Testing Therapeutic Tissue Sample Tissues Villus antagonist cell type cellular microvillus design dextran sulfate sodium induced colitis dietary control fatty acid metabolism fatty acid oxidation feeding gain of function gene function healing ileum intestinal epithelium intestinal injury loss of function meter monolayer mouse model novel nutrient absorption overexpression prevent protein expression scaffold tissue injury tool transcriptome sequencing transcriptomics treatment risk

项目摘要

The luminal surface of each epithelial cell is covered by several thousand bristles, known individually as a microvillus and collectively as the brush border. The brush border promotes efficient digestion and absorption of nutrients by increasing intestinal surface area and by acting as a scaffold for enzymes, transporters, and host defense factors. Our proposal is significant because few studies address how microvillus structures are regulated in homeostasis or intestinal disease, despite the critical importance of the intestinal brush border to normal intestinal physiology. Monogenetic diseases with disruption of the brush border present with severe diarrhea and intestinal pathology. We have reported that abnormally short ileal microvillus length is present in a subset of histologically uninflamed Crohn’s disease (CD) ileal tissue samples. This phenotype identifies CD patients at-risk for treatment-refractory disease and future development of strictures, features associated with poor clinical outcome in CD. The major objective of this application is to define mechanisms that regulate microvillus length and brush border maturation. This knowledge could help us understand how to reverse pathological changes that occur at the brush border in Crohn’s disease and other pathologic conditions of the intestine. The key preliminary data supporting this application include 1) high fat diet feeding or acute loss of Ppara in intestinal epithelial cells of mice results in short microvillus length; 2) overexpression of Ppara in intestinal epithelial cells rescues high fat diet-induced microvillus shortening; 3) experimental injury of the duodenum or distal colon of mice cause microvillus length shortening in the ileum; and 4) altered brush border ultrastructure and protein expression are observed in Crohn’s disease vs. control patient ileal biopsy tissues. Our central hypothesis is that microvillus length and brush border maturity are suppressed following high fat diet or intestinal injury and can be restored by PPARα signaling activation within intestinal epithelial cells. In Aim 1, we will determine how high fat diet and intestinal epithelial PPARα signaling alter brush border morphology, ultrastructure, and protein expression using novel conditional mouse models with Ppara gain-of-function or loss-of-function specifically in the intestinal epithelium and air-liquid interface epithelial monolayer cultures. We will also use untargeted and targeted approaches to investigate the cellular mechanisms linking microvillus length changes to PPARα signaling. In Aim 2, we will use Ppara conditional mice to determine if intestinal epithelial PPARα signaling influences inflammatory and tissue injury outcomes and injury-associated ileal brush border changes. We anticipate that completion of the proposed studies will produce the following deliverable: identification of a biological pathway and cellular mechanism that integrates host and environmental influences to modify intestinal brush border morphology and function.

每个上皮细胞的腔表面被数千根刚毛覆盖，单独称为微绒毛，统称为刷状缘。刷状缘通过增加肠道表面积和作为酶、转运蛋白和宿主防御因子的支架来促进营养物质的有效消化和吸收。我们的建议是有意义的，因为很少有研究解决微绒毛结构是如何调节的稳态或肠道疾病，尽管肠道刷状缘的正常肠道生理至关重要。刷状缘破坏的单基因疾病表现为严重腹泻和肠道病变。我们曾报道，回肠微绒毛长度异常短，存在于一个子集的组织学上未发炎的克罗恩病（CD）回肠组织样本。该表型可识别CD患者存在治疗难治性疾病和未来狭窄发展的风险，这些特征与CD临床结局不良相关。本申请的主要目的是确定调节微绒毛长度和刷状缘成熟的机制。这些知识可以帮助我们了解如何逆转克罗恩病和其他肠道病理条件中刷状缘发生的病理变化。支持这一应用的关键初步数据包括：1）高脂饮食喂养或小鼠肠上皮细胞中Ppara的急性缺失导致微绒毛长度缩短; 2）肠上皮细胞中Ppara的过表达挽救了高脂饮食诱导的微绒毛缩短; 3）小鼠十二指肠或远端结肠的实验性损伤导致回肠中微绒毛长度缩短;和4）在克罗恩病与对照患者回肠活检组织中观察到改变的刷状缘超微结构和蛋白质表达。我们的中心假设是，微绒毛长度和刷状缘成熟在高脂饮食或肠损伤后受到抑制，并且可以通过肠上皮细胞内的PPARα信号激活来恢复。在目的1中，我们将使用具有Ppara功能获得或功能丧失的新型条件性小鼠模型，特别是在肠上皮和气液界面上皮单层培养物中，确定高脂饮食和肠上皮PPARα信号传导如何改变刷状缘形态、超微结构和蛋白表达。我们还将使用非靶向和靶向方法来研究微绒毛长度变化与PPARα信号传导之间的细胞机制。在目标2中，我们将使用Ppara条件性小鼠来确定肠上皮细胞PPARα信号传导是否影响炎症和组织损伤结果以及损伤相关的回肠刷状缘变化。我们预计，完成拟议的研究将产生以下可交付成果：识别整合宿主和环境影响以改变肠道刷状缘形态和功能的生物学途径和细胞机制。