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

• 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
• 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' 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

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 克罗恩病的管理面临的挑战之一（CD；一种慢性肠炎） 是制定更有效和个性化的治疗策略。 CD很难治疗的主要原因是 因为该疾病是由遗传易感性和环境因素引起的。了解如何 与CD相关的基因环境相互作用会影响疾病结果，将为治疗的发展提供信息 策略。我们表明，小肠paneth细胞的形态表型和功能是 通过宿主遗传学和已知CD环境风险因素的综合作用进行修改，以便CD 暴露于ATG16L1 T300A多态性的患者（以及相应的遗传改良小鼠） 吸烟（关键的CD风险因素）会出现Paneth细胞异常。但是，细胞和 香烟吸烟引起的泛细胞异常的分子机制尚不清楚。我们的长期目标 是为了剖析基因环境相互作用如何影响的细胞和分子机制 克罗恩病的发展和结果。这些发现将促进CD的治疗试验设计。 该赠款的目的是确定吸烟如何诱导泛细胞异常。中央 假设是，泛滥的细胞中心和 - 超级因素共同有助于吸烟诱导 Paneth细胞缺陷。我们的理由是识别恢复Paneth Cell功能的机制将 为CD提供新的治疗机会。我们的具体目的将检验以下假设：（ AIM1） 自噬诱导挽救了吸烟引起的泛细胞异常； （AIM 2）肠道巨噬细胞是 通过吸烟激活，这反过来触发了细胞细胞凋亡。总结一下，我们将 了解自噬和肠道巨噬细胞在调节Paneth细胞功能中的作用。这 贡献很重要，因为它将建立自噬作为CD的新干预策略 Paneth细胞异常的患者。拟议的研究具有创新性，因为我们研究了 在有缺陷的Paneth细胞上的自噬信号通路，这是一种迄今未验证的过程。我们也使用 最先进的肠道干细胞培养系统，以鉴定影响Paneth的分子和细胞靶标 细胞功能。确定基因环境相互作用如何调节关键疾病的机制 - 相关的细胞表型将为其他炎症性疾病提供洞察力。