Systems biology approaches to understand human disease signaling networks
The overall goal in the laboratory is to discover and understand the function of important mediators and effectors involved in innate (autophagy, phagocytosis) and adaptive (T cell activation) immunity. Especially of interest are the cellular components and regulatory networks that interact dynamically within temporal, spatial, and pathophysiological contexts of immunity. We are pursuing integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays and computational methods.
Using these approaches, we are interested in several questions relating to Crohn’s disease and type 1 diabetes (T1D). With regard to Crohn’s disease, we are (1) using perturbational profiling by microbial factors to determine how ATG16L1 T300A is involved in Crohn’s disease susceptibility in the context of interactions with the environment (microbes); (2) unraveling underlying mechanisms of phenotypes associated with ATG16L1 T300A in non-canonical autophagy pathways that involve secretion; (3) identifying the molecular determinants of ATG16L1 T300A that contribute to risk of Crohn’s disease; and (4) integrating ATG16L1 *300A-specific signatures and building associated network modules relevant for Crohn’s disease to gain insights into autophagy-associated phenotypes involved in Crohn’s disease pathogenesis.
Work in the area of T1D is focused on the role of the microbiome in disease. Specifically, we are working to analyze the enteric virome in relation to T1D and to define viruses associated with T1D. To accomplish this, we are analyzing both total RNA from stool and DNA in virus-like particle (VLP) preps, and are collaborating to relate robust data on the bacterial microbiome to any observed changes in the virome. In a separate project, we are seeking to identify the changes in the gut microbiota that are introduced by feeding of extensively hydrolyzed milk formula (eHF), and determining how these changes contribute to the protection of children at risk for T1D from beta-cell autoimmunity. Toward this end, we are assessing the impact of the maternal microbiome composition on the early microbial colonization of the gut of newborns, determining the impact of the eHF dietary intervention on the intestinal microbiome development of infants, and performing an integrative analysis of the microbiome trajectory data with other data types collected by the earlier study titled Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity, led by Dr. Mikael Knip.
We are also working to identify early therapeutic leads in the context of Crohn’s disease in the hopes of accelerating treatment. We are using a combination of physiologically relevant cell-based assays and computational analyses to understand disease pathophysiology by identifying pathways regulated by genetic variants implicated in Crohn’s disease. We validate our results in human cells and novel mouse models based on genetic variants identified in patients with Crohn’s disease. Human genetics and pathways that we uncover in these investigations yield hypotheses about candidate targets for therapeutic intervention.
1. Huett A, Heath RJ, Begun J, Sassi SO, Baxt LA, Vyas JM, Goldberg MB, Xavier RJ. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe. 2012;12(6):778-90. PMCID:
2. Shoji-Kawata S, Sumpter R, Leveno M, Campbell GR, Zou Z, Kinch L, Wilkins AD, Sun Q, Pallauf K, MacDuff D, Huerta C, Virgin HW, Helms JB, Eerland R, Tooze SA, Xavier R, Lenschow DJ, Yamamoto A, King D, Lichtarge O, Grishin NV, Spector SA, Kaloyanova DV, Levine B. Identification of a candidate therapeutic autophagy-inducing peptide. Nature. 2013;494(7436):201-6. PMCID:PMC3788641
3. Smeekens SP, Ng A, Kumar V, Johnson MD, Plantinga TS, van Diemen C, Arts P, Verwiel ET, Gresnigt MS, Fransen K, van Sommeren S, Oosting M, Cheng SC, Joosten LA, Hoischen A, Kullberg BJ, Scott WK, Perfect JR, van der Meer JW, Wijmenga C, Netea MG, Xavier RJ. Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans. Nat Commun. 2013;4:1342. PMID: 23299892. PMCID:PMC3625375
4. Shaw SY, Tran K, Castoreno AB, Peloquin JM, Lassen KG, Khor B, Aldrich LN, Tan PH, Graham DB, Kuballa P, Goel G, Daly MJ, Shamji AF, Schreiber SL, Xavier RJ. Selective modulation of autophagy, innate immunity, and adaptive immunity by small molecules. ACS Chem Biol. 2013;8(12):2724-33. PMCID:PMC3951132 [Available on 2014/12/20]
5. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O’Neill LA.Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013 Apr 11;496(7444):238-42.PMCID:PMC4031686