Forward Genetic Analysis of Intestinal Homeostasis

摘要 炎症性肠病是一种使人衰弱的慢性疾病，它可以影响肠道的任何部分。 肠，经常有复发和缓解过程。在美国，大约有1.4 有1000万人患有溃疡性结肠炎或克罗恩病。结肠的炎症反应 和小肠可能导致疼痛，感染和出血，最终导致医疗保健负担， 增加住院率、急诊手术率，最重要的是增加死亡率。虽然超- 对肠道微植物群的炎症反应肯定在IBD的病因学中起作用，确切地说， 然而，炎症性肠病的病因学尚不清楚， 自然 粘膜免疫系统的维持有许多水平，如在人类中所见。 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 上皮增殖、凋亡、自噬和细胞代谢。任何这些系统的扰动 导致肠内稳态的缺陷并最终导致病理学。 我最近的研究着眼于维持肠道内稳态所必需的遗传因素。 使用随机诱变小鼠的筛选，我已经确定并绘制了30多个候选基因， 对小鼠实验性结肠炎表现出易感性或抗性的新型小鼠品系。一个这样 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 修饰小鼠，其中关键神经酰胺代谢基因（Degs 2）缺失或突变，以阐明神经酰胺代谢的机制。 了解这些途径及其调节。我研究的最终目标是确定新的 这些途径可以更好地治疗肠道疾病，如克罗恩病和溃疡性结肠炎。

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.