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.
The proposed research is relevant to the public health because Crohn?s disease, which is increasing in prevalence worldwide, represents a major national cost measured by both patient suffering and economic burden. Despite significant advances in care, clinical trial data demonstrate remission rates of Crohn?s disease is at best of 40%. Strategies that restore Paneth cell function represent a novel therapeutic direction for CD. We have shown that cigarette smoking induces functional defects in Paneth cells. Despite the available cigarette smoking cessation programs, active smokers constitute ~40% of all Crohn?s disease patients, so understanding how cigarette smoking triggers Paneth cell defect can lead to development of intervention strategies. Upon conclusion, we will understand the roles of Paneth cell-intrinsic factor (autophagy) and Paneth cell-extrinsic factor/cell type (macrophages) in regulating smoking-induced Paneth cell abnormality.
