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.

抽象的正如我们最近表明的那样，肥胖被低估的影响之一是抑制肠道先天免疫在超重/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- 我们进一步表明，用西方饮食（WD）喂养的野生型小鼠也出现了潘氏细胞缺陷。摄入 WD 会导致微生物介导的脱氧胆酸（一种次级胆汁酸）增加，它激活回肠中的 FXR 通路以及肠上皮中的 FXR 激活。介导的 I 型干扰素在骨髓细胞中的激活，共同引发潘氏细胞缺陷。在将这些发现转化为临床之前需要解决的问题包括个人饮食如何影响潘氏细胞功能的成分，以及长期食用 WD 是否会导致潘氏细胞缺陷单独饮食改变是不可逆转的，我们的长期目标是剖析其细胞和分子机制。这些发现将如何影响 WD 的肠道干细胞 (ISC) 和潘氏细胞生物学。促进针对肠道先天免疫功能障碍的肥胖患者的试验设计该提案的目的。确定WD如何诱发潘氏细胞异常的中心假设是长期的。由于潘氏细胞能力减弱，食用膳食果糖会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]）我们的理由是这种识别。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，例如患有炎症性肠病和移植物抗宿主病的患者，其中潘氏细胞发挥着重要作用我们的初步数据表明，仅饮食中摄入果糖就足够了。触发潘氏细胞缺陷，并且长期（≥12个月）WD食用后潘氏细胞缺陷是通过改用标准饮食是无法逆转的。我们的具体目标将测试以下假设：（目标 1）如何实现。膳食果糖直接诱发潘氏细胞缺陷；（目标2）长期食用WD会损害潘氏细胞以及 ISC 修复和补充有缺陷的潘氏细胞的能力根据结论，我们。将了解膳食果糖在调节潘氏细胞和 ISC 功能中的作用。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拟议的研究具有创新性，因为我们调查了长期暴露于不良饮食对健康的影响。肠道先天免疫，这是一个迄今为止未经检验的过程，我们还使用最先进的 ISC 培养系统和 scRNA-seq 和 scATAC-seq 技术可识别影响潘氏细胞和细胞的分子和细胞靶标确定饮食如何调节关键疾病相关细胞表型的机制。提供对其他炎症性疾病的深入了解。