IKKα调控肠道炎症及肠炎相关性大肠癌的机理研究

作为控制炎症反应的关键转录因子，NF-κB在肠道炎症和大肠癌的发病机理中发挥重要作用。小鼠肠道中条件性剔除经典的NF-κB通路会破坏天然免疫的平衡，从而导致肠道炎症。然而非经典NF-κB通路在肠道炎症和炎性相关大肠癌中的功能尚未明确。IKKα作为一个IKK激酶亚基既可激活经典NF-κB通路，亦可独立激活非经典NF-κB通路，来参与调控T细胞分化，外周淋巴发育等。我们前期研究已表明在表皮细胞中IKKα可通过不依赖NF-κB的下游信号来抑制肿瘤发生。多种肿瘤中均有IKKα基因突变的报道，但IKKα在肠道表皮细胞和肠道免疫中的功能尚不明晰。我们拟利用肠道表皮细胞和小鼠的肠炎及大肠癌模型，来研究IKKα在肠道表皮细胞中对经典、非经典NF-κB通路和下游炎症因子表达的调控，以及对天然细胞的招募和肠道免疫微环境形成的影响，进而确认IKKα激酶在肠道炎症及炎症相关性肠癌发病机制中的作用。

NF-κB is a master regulator of inflammatory responses in responses to a variety of stimuli in different types of tissues and cells. The pivotal role of NF-κB in regulating colon inflammation and colitis-associated colon cancer has been extensively studied and validated in different models. Conditional knockout mouse model has validated the key function of classical NF-κB signaling in maintaining intestine immune homeostasis. By contrast, the role of noncanonical NF-κB signaling in colon inflammation and colitis-associated cancer is largely unknown. The classical NF-κB signaling is controlled by the IκB Kinase (IKK) complex composed of IKKα, IKKβ, and NEMO. While classical NF-κB activation rely more on IKKβ than IKKα for proper activation, noncanonical NF-κB signaling depend on IKKα homodimer for downstream signaling transduction and physiological functions such as secondary lymphoid organ development, bone metabolism, and T cell differentiation. In our previous studies, we have identified a tumor suppressor function of IKKα in epithelial tissues through both NF-κB dependent and independent manners. Although IKKα gene mutations have been reported in human skin lesions and cancer genome sequencing, the function of IKKα in intestinal epithelial cells and colon inflammation is still not well understood. Based on our previous studies, we hypothesize that IKKα regulate intestine inflammation and colitis-associated cancer through noncanonical NF-κB signaling. To test this hypothesis, we propose to set up chemical-induced colitis and colon cancer mouse model with in vivo knockdown of IKKα expression, and to study the function of IKKα in controlling classical and noncanonical NF-κB signaling in intestine epithelial cells and immune cells, maintaining local immune microenvironment homeostasis, and protecting mice from inflammation and colitis-associated cancer. We will further investigate IKKα expression pattern in human colon cancer tissues and the correlation between IKKα expression and disease progression, thereby determining the clinical relevance of our study. The proposed study will define the physiological function of IKKα in colon inflammation and cancer, and may provide new sights for prevention and therapeutics for inflammation-associated colitis and colon cancer.