Cellular and molecular mechanisms of cigarette smoking-induced Paneth cell abnormality

吸烟引起潘氏细胞异常的细胞和分子机制

基本信息

批准号：
10192716
负责人：
Ta-Chiang Liu
金额：
$ 35.44万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192716
关键词：
Abnormal Cell Acute Affect Apoptosis Autophagocytosis Caring Cell Culture System Cell Death Cell Differentiation process Cell Survival Cell physiology Cells Cellular Morphology Chronic Clinical Clinical Trials Coculture Techniques Complex Cost Measures Crohn&apos s disease Data Defect Development Disease Disease Outcome Disease remission Economic Burden Environmental Risk Factor Excision Exposure to Functional disorder Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Risk Goals Grant Hematology Homeostasis Immune In Vitro Infection Inflammatory Inflammatory Bowel Diseases Injury Intervention Intestines Intrinsic factor Knock-in Knock-out Knockout Mice Knowledge Lead Medical Modeling Molecular Molecular Target Morphology Mus Natural Immunity Operative Surgical Procedures Organoids Outcome Paneth Cells Pathology Pathway interactions Patients Pattern Pharmacology Phase Phenotype Prevalence Process Public Health Recurrence Research Risk Factors Role Secretory Cell Signal Pathway Signal Transduction Small Intestines Smoke Smoker Smoking Stimulus Susceptibility Gene System Testing Therapeutic Intervention Therapy trial Variant Wild Type Mouse Work cell type cellular targeting chemokine cigarette smoke cigarette smoking combinatorial cytokine endoplasmic reticulum stress experimental study gene environment interaction in vivo inflammatory disease of the intestine inhibition of autophagy innovation insight intestinal injury macrophage mouse model new therapeutic target novel novel therapeutics pathogen personalized medicine programs response smoking cessation stem cells therapeutic development therapeutic target therapy design therapy development treatment strategy

项目摘要

ABSTRACT One of the challenges for the management of Crohn’s disease (CD; a chronic intestine inflammatory disorder) is to develop more efficient and personalized treatment strategies. A major reason why CD is difficult to treat is because the disease is induced by both genetic susceptibility and environmental factors. Understanding how CD-relevant gene-environment interaction affects disease outcome will inform the development of therapeutic strategies. We showed that the morphologic phenotype and function of small intestinal Paneth cells are modifiable by integrated effects from both host genetics and known CD environmental risk factor, such that CD patients (and corresponding genetic modified mice) who harbor ATG16L1 T300A polymorphism when exposed to cigarette smoking (a key CD risk factor) develop Paneth cell abnormality. However, the cellular and molecular mechanisms of cigarette smoking-induced Paneth cell abnormality are unknown. Our long-term goal is to dissect the cellular and molecular mechanisms of how gene-environment interactions affect the development and outcome of Crohn’s disease. These discoveries will facilitate design of therapy trials for CD. The objective of this grant is to determine how cigarette smoking induces Paneth cell abnormality. The central hypothesis is that both Paneth cell-intrinsic and –extrinsic factors collectively contribute to smoking-induced Paneth cell defects. Our rationale is that identification of the mechanism(s) to restore Paneth cell function will offer new therapeutic opportunities for CD. Our specific aims will test the following hypotheses: (Aim1) Autophagy induction rescues smoking-induced Paneth cell abnormality; (Aim 2) Intestinal macrophages are activated by cigarette smoking, which in turn triggers Paneth cell apoptosis. Upon conclusion, we will understand the role for autophagy and intestinal macrophages in modulating Paneth cell function. This contribution is significant since it will establish autophagy induction as a new intervention strategy for CD patients with Paneth cell abnormality. The proposed research is innovative because we investigate the effect of autophagy signaling pathways on defective Paneth cells, a heretofore-unexamined process. We also use state-of-the-art intestinal stem cell culture system to identify molecular and cellular targets that affect Paneth cell functions. Identifying the mechanisms of how gene-environment interactions regulate a key disease- relevant cellular phenotype will provide insight into other inflammatory disorders.

抽象的克罗恩病（CD；一种慢性肠道炎症性疾病）治疗面临的挑战之一制定更高效、个性化的治疗策略是CD难以治疗的一个主要原因。因为这种疾病是由遗传易感性和环境因素共同诱发的。 CD 相关基因-环境相互作用影响疾病结果将为治疗方法的开发提供信息我们发现小肠潘氏细胞的形态表型和功能是不同的。可通过宿主遗传学和已知 CD 环境风险因素的综合效应进行修改，例如 CD 暴露时携带 ATG16L1 T300A 多态性的患者（和相应的转基因小鼠）吸烟（CD 的一个关键危险因素）会导致潘氏细胞异常，但是，细胞和吸烟引起潘氏细胞异常的分子机制尚不清楚，我们的长期目标尚不清楚。是剖析基因-环境相互作用如何影响的细胞和分子机制这些发现将有助于克罗恩病的治疗试验的设计。这笔赠款的目的是确定吸烟如何导致潘氏细胞异常。假设潘氏细胞内在因素和外在因素共同导致吸烟引起的我们的理由是，识别恢复潘氏细胞功能的机制将有助于恢复潘氏细胞功能。为 CD 提供新的治疗机会。我们的具体目标将检验以下假设：（目标 1）自噬诱导可挽救吸烟引起的潘氏细胞异常（目标 2）肠道巨噬细胞由吸烟激活，进而引发潘氏细胞凋亡。了解自噬和肠道巨噬细胞在调节潘氏细胞功能中的作用。贡献是重大的，因为它将建立自噬诱导作为 CD 的新干预策略这项研究具有创新性，因为我们研究了潘氏细胞异常的影响。我们还使用有缺陷的潘氏细胞的自噬信号通路，这是一个迄今为止未经检验的过程。最先进的肠道干细胞培养系统，用于识别影响潘氏的分子和细胞靶标确定基因-环境相互作用如何调节关键疾病的机制。相关的细胞表型将提供对其他炎症性疾病的深入了解。