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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.

摘要肥胖的一个未被充分认识的影响是肠道先天免疫的抑制，正如我们最近所展示的那样在超重/肥胖患者中，使用潘氏细胞表型（作为潘氏细胞功能的替代物）作为证据- 的概念。用西方饮食（WD）喂养的野生型小鼠也出现潘氏细胞缺陷。我们进一步研究发现 WD消耗导致微生物群介导的脱氧胆酸（二级胆汁酸）增加，从而激活回肠中的FXR通路。肠上皮中的FXR活化，以及FXR- 介导的髓样细胞中的I型干扰素活化，共同触发潘氏细胞缺陷。临界在将这些发现转化为临床之前，需要解决的问题包括：影响潘氏细胞功能的成分，如果长期WD消耗使潘氏细胞缺陷不可逆的饮食转变。我们的长期目标是剖析细胞和分子机制 WD消耗如何影响肠干细胞（ISC）和潘氏细胞生物学。这些发现将为肠道先天免疫功能障碍的肥胖患者的试验设计提供便利。本提案的目的是为了确定WD消耗如何诱导潘氏细胞异常。核心假设是，膳食果糖消耗由于潘氏细胞能力降低而导致潘氏细胞缺陷补充（通过潘氏细胞本身和/或肠干细胞[ISC]）。我们的理论是，恢复潘氏细胞功能的机制将为许多患者提供新的治疗机会，例如那些患有炎症性肠病和移植物抗宿主病患者，其中潘氏细胞发挥了在发病机制中发挥关键作用。我们的初步数据表明，饮食中果糖的摄入量是足够的触发潘氏细胞缺陷，长期（≥12个月）WD消耗后潘氏细胞缺陷，不可逆的转换到标准饮食。我们的具体目标将测试以下假设：（目标1）如何饮食果糖直接诱导潘氏细胞缺陷;（目的2）长期WD消费将损害潘氏细胞以及ISC修复和补充缺陷潘氏细胞的能力。在结束时，我们将了解膳食果糖在调节潘氏细胞和ISC功能中的作用。这种贡献因为它将建立肠上皮果糖催化剂和相关基因作为治疗目标的这项拟议中的研究是创新的，因为我们调查了长期暴露于不良饮食对肠道先天免疫，一个迄今未被研究过的过程。我们还使用最先进的ISC培养系统， scRNA-seq和scATAC-seq技术来鉴定影响潘氏细胞的分子和细胞靶标， ISC职能。确定饮食如何调节关键疾病相关细胞表型的机制将提供对其他炎症性疾病的深入了解。