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.
Genetic approaches have contributed greatly to the understanding of intestinal homeostasis demonstrating novel regulators of inflammation and intestinal function. The combination of whole genome mutagenesis, massively parallel exome sequencing and traditional genetics in mice allows for the rapid development of colitis susceptible and resistant phenotypes. This proposal seeks to characterize how a lipid synthesis gene (Degs2) found through forward genetic analysis and determine how it controls intestinal homeostasis, inflammation and cellular metabolism.
| McAlpine, William; Sun, Lei; Wang, Kuan-Wen et al. (2018) Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. Proc Natl Acad Sci U S A 115:E11523-E11531 |
| McAlpine, William; Wang, Kuan-Wen; Choi, Jin Huk et al. (2018) The class I myosin MYO1D binds to lipid and protects against colitis. Dis Model Mech 11: |
| Miyata, Naoteru; Morris, Lindsey L; Chen, Qing et al. (2018) Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation. Cell Rep 24:2342-2355 |
| Turer, Emre; McAlpine, William; Wang, Kuan-Wen et al. (2017) Creatine maintains intestinal homeostasis and protects against colitis. Proc Natl Acad Sci U S A 114:E1273-E1281 |
| Zhang, Zhao; Turer, Emre; Li, Xiaohong et al. (2016) Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. Proc Natl Acad Sci U S A 113:E6418-E6426 |
