Massachusetts General Hospital
Center for Computational & Integrative Biology
185 Cambridge Street - Simches 7222
Boston, MA 02114
The overall goal in the laboratory is to discover and understand the function of important mediators and effectors involved in innate (autophagy, pathogen-containing vacuole) and adaptive (T cell activation) immunity. Especially of interest are the cellular components and regulatory networks which interact dynamically within temporal, spatial, and pathophysiological contexts of innate immunity. We are pursuing integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays (RNAi and cDNA screens) and computational methods. Using these approaches we are interested in addressing the following issues: 1) the mechanisms by which autophagy regulates innate and adaptive immunity, 2) the roles of NOD/LRR domains in sensing microbial effectors, and 3) how innate immune pathways are dysregulated in mucosal immunity. The adaptive immunity program focuses on elucidating signal transduction pathways coordinated by the CARMA/Dlg family of scaffold proteins.
Crohn’s disease and ulcerative colitis are debilitating inflammatory diseases of the gastrointestinal tract collectively known as inflammatory bowel diseases. Among complex diseases, genetics has been particularly successful in the identification of genes for IBD, with recent efforts in genome-wide association studies bringing the total number of loci to >100. These studies have highlighted the significance of the relationship between intracellular responses to microbes and the regulation of adaptive immunity in the pathogenesis of IBD. With rapid progress in human genetics it has become clear that a major challenge in the study of complex genetic traits is to determine how disease genes and their corresponding alleles exert their influence on the biology of health and disease. The lab focuses on applying novel genomic, genetic, and chemical biology approaches to gain insights into the function of genetic variants underlying common inflammatory disease and to explore the potential for reversing the effects of susceptibility alleles.
Orvedahl A, Sumpter R, Jr., Xiao G, Ng A, Zou Z, Tang Y, Narimatsu M, Gilpin C, Sun Q, Roth M, Forst CV, Wrana JL, Zhang YE, Luby-Phelps K, Xavier RJ, Xie Y, Levine B. 2011. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480: 113-7.
Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, Boucher G, Ripke S, Ellinghaus D, Burtt N, Fennell T, Kirby A, Latiano A, Goyette P, Green T, Halfvarson J, Haritunians T, Korn JM, Kuruvilla F, Lagace C, Neale B, Lo KS, Schumm P, Torkvist L, Dubinsky MC, Brant SR, Silverberg MS, Duerr RH, Altshuler D, Gabriel S, Lettre G, Franke A, D'Amato M, McGovern DP, Cho JH, Rioux JD, Xavier RJ, Daly MJ. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43: 1066-73.
Khor B, Gardet A, Xavier RJ. 2011. Genetics and pathogenesis of inflammatory bowel disease. Nature 474: 307-17.
Heath RJ, Leong JM, Visegrady B, Machesky LM, Xavier RJ. 2011. Bacterial and host determinants of MAL activation upon EPEC infection: the roles of Tir, ABRA, and FLRT3. PLoS Pathog 7: e1001332.
Ng AC, Eisenberg JM, Heath RJ, Huett A, Robinson CM, Nau GJ, Xavier RJ. 2011. Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity. Proc Natl Acad Sci U S A 108 Suppl 1: 4631-8.
Last Update: 12/13/2012