Forward Genetic Analysis of Intestinal Homeostasis

摘要 炎症性肠病是一种使人虚弱的慢性疾病，可影响 肠病，常有复发和缓解的病程。在美国，大约有1.4 数百万人受到溃疡性结肠炎或克罗恩病的影响。由此导致的结肠炎 小肠会导致疼痛、感染和出血，这最终会导致医疗保健负担 住院和紧急手术增加，最重要的是死亡率增加。尽管一个超级- 肠道微生物区系的炎症反应在IBD的病因中肯定起着作用，确切的 然而，炎症性肠病的病因还不是很清楚，而且肯定是多因素影响的。 大自然。 粘膜免疫系统的维持有很多层次，就像在人类身上看到的那样。 遗传学和实验小鼠模型。这些系统包括免疫和生长因子以及 上皮细胞增殖、凋亡、自噬和细胞代谢。这些系统中的任何一个的扰动 导致肠道内环境平衡失调，最终导致病理改变。 我最近的研究着眼于维持肠道内环境稳定所必需的遗传因素。 使用随机突变的小鼠的筛选，我已经识别并绘制了30多个候选基因 对小鼠实验性结肠炎表现出易感性或抗药性的新型小鼠品系。这样的一个 意想不到的途径涉及神经酰胺和植物神经酰胺的从头合成。我计划用基因技术 修饰的小鼠，其中一个关键的神经酰胺代谢基因(Degs2)被缺失或突变，以阐明一种机制 了解这些途径及其调控。我研究的最终目标是确定新的 途径，可以更好地治疗肠道疾病，如克隆氏症和溃疡性结肠炎。

Abstract Inflammatory bowel disease is a debilitating chronic condition, which can affect any part of the intestine, often having by a relapsing and remitting course. In the United States, there are approximately 1.4 million people are affected by ulcerative colitis or Crohn's disease. The resulting inflammation in the colon and small intestine can lead to pain, infections and bleeding, which ultimately leads to a healthcare burden of increased hospitalizations, emergency surgeries and most importantly increased mortality. Although a hyper- inflammatory response to the intestinal micro flora certainly plays a role in the etiology of IBD, the exact etiology of inflammatory bowel disease, however, is not well understood and is most certainly multifactorial in nature. The maintenance of the mucosal immune system has many levels as has been seen in human genetics and experimental mouse models. These systems include immune and growth factor as well as epithelial proliferation, apoptosis, autophagy and cellular metabolism. Perturbation of any of these systems results in a defect of intestinal homeostasis and ultimately resulting in pathology. My recent studies have looked at the genetic factors necessary for maintaining intestinal homeostasis. Using a screen of randomly mutagenized mice, I have identified and mapped candidate genes for over 30 novel mouse strains that show either susceptibility or resistance to mouse experimental colitis. One such unexpected pathway involves the de novo synthesis of ceramide and phytoceramide. I plan to use genetically modified mice in which a key ceramide metabolic gene (Degs2) is deleted or mutated to elucidate a mechanistic understanding of these pathways and their regulation. The ultimate goal of my research is to determine new pathways, which can be targeted to better treat intestinal diseases, such as Crohn's and ulcerative colitis.