Dietary modulation of Paneth cells

潘氏细胞的饮食调节

基本信息

批准号：
10718365
负责人：
Ta-Chiang Liu
金额：
$ 50.69万
依托单位：
WASHINGTON UNIVERSITY
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：
2023-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718365
关键词：
Abnormal Cell Address Affect Area Behavior Bile Acids CD11 Antigens Catabolism Cell Count Cell Culture System Cell Differentiation process Cell Survival Cell physiology Cells Cellular Stress Cellular biology Clinic Clinical Consumption Cost Measures Data Defect Deoxycholic Acid Diet Dietary Component Disease Economic Burden Enterocytes Environmental Risk Factor Epigenetic Process Epithelial Cells Exposure to Fatty acid glycerol esters Fructose Functional disorder General Population Genes Goals High Fat Diet Homeostasis Human In Vitro Individual Infection Inflammatory Inflammatory Bowel Diseases Injury Interferon Activation Interferon Type I Intervention Intestines Ketohexokinase Knockout Mice Knowledge Link Longevity Mediating Metabolic Metabolism Modeling Molecular Molecular Target Morphology Mucous Membrane Mus Myeloid Cells Natural Immunity Natural regeneration Obesity Organoids Overweight Paneth Cells Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Play Prevalence Process Public Health Quality of life Receptor Activation Receptor Signaling Reducing diet Reporter Reporting Repression Research Risk Role Severities Small Intestines Techniques Testing Translating Unhealthy Diet Wild Type Mouse base cell type cellular targeting cohort diet-induced obesity dietary endoplasmic reticulum stress epigenetic profiling epigenetic regulation farnesoid X-activated receptor graft vs host disease gut inflammation ileum impaired capacity in vivo innovation insight intestinal epithelium microbiota mouse model novel novel therapeutics obese patients obesogenic prevent progenitor programs receptor repaired sensor single cell technology single-cell RNA sequencing stem cell differentiation stem cell function stem cell homeostasis stem cells therapeutic target therapy design therapy development transcriptomic profiling transcriptomics trial design type I interferon receptor western diet

项目摘要

ABSTRACT One of the underappreciated effect of obesity is the repression of gut innate immunity, as we recently showed in overweight/obese patients, using Paneth cell phenotype (as a surrogate for Paneth cell function) as a proof- of-concept. Wild type mice fed with western diet (WD) also developed Paneth cell defects. We further showed that WD consumption results in microbiota-mediated increase in deoxycholic acid (a secondary bile acid), which activates the FXR pathway in the ileum. FXR activation in the intestinal epithelium, as well as FXR- mediated type I interferon activation in myeloid cells, collectively trigger Paneth cell defects. The critical questions that need to be addressed before translating these findings to clinic include how individual dietary components that impact Paneth cell function, and if long-term WD consumption renders Paneth cell defects irreversible to dietary switch alone. Our long-term goal is to dissect the cellular and molecular mechanisms of how WD consumption affect the intestinal stem cell (ISC) and Paneth cell biology. These discoveries will facilitate design of trials for obese patients with gut innate immunity dysfunction. The objective of this proposal is to determine how WD consumption induces Paneth cell abnormality. The central hypothesis is that long-term consumption of dietary fructose result in Paneth cell defect due to diminished capacity of Paneth cell replenishment (by Paneth cells themselves and/or intestinal stem cells [ISC]). Our rationale is that identification of the mechanism(s) to restore Paneth cell function will offer new therapeutic opportunities for many patients, such as those with inflammatory bowel disease and graft versus host disease, of which Paneth cells play a critical role in pathogenesis. Our preliminary data suggest that dietary fructose consumption alone is sufficient to trigger Paneth cell defects, and that Paneth cell defects after long-term (≥12 months) WD consumption are not reversible by switching to standard diet. Our specific aims will test the following hypotheses: (Aim1) How dietary fructose directly induces Paneth cell defects; (Aim 2) Long-term WD consumption will impair the capacity of Paneth cells as well as ISCs to repair and replenish defective Paneth cells. Upon conclusion, we will understand the role for dietary fructose in modulating Paneth cell and ISC function. This contribution is significant since it will establish intestinal epithelial fructose catabolism and associated genes as therapeutic targets. The proposed research is innovative because we investigate how long-term exposure to poor diet on gut innate immunity, a heretofore-unexamined process. We also use state-of-the-art ISC culture system and scRNA-seq and scATAC-seq techniques to identify molecular and cellular targets that affect Paneth cell and ISC functions. Identifying the mechanisms of how diets regulate a key disease-relevant cellular phenotype will provide insight into other inflammatory disorders.

抽象的肥胖的潜在效果之一是肠道先天免疫的表达在超重/肥胖的患者中，使用Paneth细胞表型（作为Paneth细胞功能的替代物）作为证明概念。喂西方饮食（WD）的野生型小鼠也会产生泛细胞缺陷。我们进一步显示 WD消耗导致微生物群介导的脱氧胆酸（一种胆汁酸）的增加，激活回肠中的FXR途径。肠上皮的FXR激活以及FXR- 介导的I型干扰素在髓样细胞中的激活，共同触发了Paneth细胞缺陷。关键在将这些发现转换为诊所之前需要解决的问题包括个体饮食影响Paneth细胞功能的组件，如果长期WD消耗使Paneth细胞缺陷呈现仅饮食转换不可逆。我们的长期目标是剖析细胞和分子机制 WD消耗如何影响肠道干细胞（ISC）和Paneth细胞生物学。这些发现会促进对肠道先天免疫功能障碍的肥胖患者的试验设计。该提议的目的是确定WD消耗如何诱导Paneth细胞异常。中心假设是长期饮食果糖的消耗导致泛细胞缺陷，由于泛细胞的能力降低补充（通过Paneth细胞本身和/或肠干细胞[ISC]）。我们的理由是身份证明恢复Paneth Cell功能的机制将为许多患者提供新的治疗机会，例如患有炎症性肠病和移植物与宿主疾病的患者，其中Paneth细胞发挥在发病机理中的关键作用。我们的初步数据表明，仅饮食果糖消耗就足够了为了触发Paneth细胞缺陷，并且长期（≥12个月）WD消耗后的Paneth细胞缺陷为通过改用标准饮食不可逆转。我们的具体目标将检验以下假设：（ AIM1）如何饮食果糖直接诱导Paneth细胞缺陷；（AIM 2）长期WD消耗会损害 Paneth细胞以及ISC修复和复制有缺陷的Paneth细胞的能力。总结一下，我们将了解饮食果糖在调节Paneth细胞和ISC功能中的作用。这个贡献是意义重大，因为它将建立肠上皮果糖分解代谢和相关基因作为治疗目标。拟议的研究具有创新性，因为我们研究了长期暴露于饮食不佳的情况下肠道天生的免疫力，迄今为止毫无证实的过程。我们还使用最先进的ISC文化系统和 SCRNA-SEQ和SCATAC-SEQ技术，以识别影响Paneth Cell和的分子和细胞靶标 ISC功能。确定饮食如何调节与疾病相关的关键细胞表型的机制将提供有关其他炎症性疾病的见解。