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

摘要 克罗恩病（CD;一种慢性肠道炎症性疾病）管理的挑战之一 是开发更有效和个性化的治疗策略。CD难以治疗的主要原因是 因为这种疾病是由遗传易感性和环境因素共同诱发的。了解如何 CD相关基因-环境相互作用影响疾病结局将为治疗药物的开发提供信息。 战略布局我们发现，小肠潘氏细胞的形态表型和功能， 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ATG 16 L1 T300 A多态性的患者（和相应的遗传修饰小鼠） 吸烟（一个关键的CD风险因素）发展潘氏细胞异常。然而，细胞和 吸烟诱导潘氏细胞异常的分子机制尚不清楚。我们的长期目标 是剖析基因-环境相互作用如何影响细胞和分子机制， 克罗恩病的发展和结果。这些发现将促进CD治疗试验的设计。 这项资助的目的是确定吸烟如何诱导潘氏细胞异常。中央 一种假说认为，潘氏细胞内源性和外源性因素共同促进了吸烟诱导的 潘氏细胞缺陷。我们的基本原理是，恢复潘氏细胞功能的机制的鉴定将 为CD提供了新的治疗机会。我们的具体目标将测试以下假设：（目标1） 自噬诱导挽救吸烟诱导的潘氏细胞异常;（目的2）肠巨噬细胞是 吸烟会激活这种细胞，进而引发潘氏细胞凋亡。在结束时，我们将 了解自噬和肠道巨噬细胞在调节潘氏细胞功能中的作用。这 这一贡献是重要的，因为它将建立自噬诱导作为CD的新干预策略 潘氏细胞异常患者。这项研究是创新的，因为我们调查了 有缺陷的潘氏细胞上的自噬信号通路，这是一个迄今未被研究的过程。我们还使用 最先进的肠道干细胞培养系统，用于识别影响Paneth的分子和细胞靶点 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- 相关的细胞表型将提供对其他炎性疾病的了解。

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.