BADERC Welcome

Ramnik Xavier, M.D., Ph.D

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 which 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.

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 patho-physiological 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 questions 1) what are the mechanisms by which autophagy regulates innate and adaptive immunity 2) the role of leucine rich repeat domains in sensing microbial effectors 3) how are innate immune pathways dysregulated in inflammatory bowel disease. The adaptive immunity program focuses elucidating signal transduction pathways coordinated by the CARMA and Dlg1 family of scaffold proteins.

We hope to gain additional insights about the immune system in terms of the underlying interaction and regulatory networks that define functional modules at the host-microbe interface and tumor immunity. In addition the team of computational biologists and mathematicians in the group are developing new algorithms to generate testable hypotheses and models using information from genome-wide studies, high-throughput screens and functional perturbation studies to gain insights into molecular and regulatory mechanisms in immunity and autoimmune disorders.

Functional analysis of novel IBD loci/genes
Crohn's disease (CD) and ulcerative colitis (UC) are idiopathic inflammatory disorders of the gastrointestinal tract known as the inflammatory bowel diseases (IBD). There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to disease. Ongoing collaborative studies with NIDDK Genetics Consortium have resulted in the discovery of novel IBD loci in Crohn's disease. We are currently developing molecular approaches (knock-out/knock-in mice, biochemistry, proteomics and computational approaches) to identify the functional implications of the novel regulatory and structural polymorphisms discovered in IBD. We are also interested in the development of network construction algorithms which integrate into a Bayesian framework physical and genetic associations using clinical and genotype data from patients and multiple high-throughput datasets to extract static and dynamic features for predicting phenotypic effects of temporal gene perturbation in tissues and cell types relevant to the disease state.

References:

Krishnan MN, Ng A, Sukumaran B, Gilfoy FD, Uchil PD, Sultana H, Brass AL, Adametz R, Tsui M, Qian F, Montgomery RR, Lev S, Mason PW, Koski RA, Elledge SJ, Xavier RJ* Agaisse H*, Fikrig E*. Whole genome RNA interface screening for human genes involved in West Nile virus. Nature 2008 Sep 11;455(7210):242-5. (Co-senior author)
McCarroll SA, Huett A, Kuballa P, Chilewski S, Landry A, Goyette P, Zody MC, Hall JL, Brant SR, Cho JH, Duerr R, Silverberg MS, Taylor KD, Rioux J, Altshuler DM, Daly MJ*, Xavier RJ*. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genetics 2008 Aug 24; Epub ahead of print.
Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ. Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant. PLos ONE 2008;3(10):e3991.
Hitomi J, Christofferson DE, Ng A, Jianhua Y, Degterev A, Xavier RJ, Yuan J. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway by a genome wide siRNA screen. Cell 2008; Dec 26;135(7):1311-1323.
Huett A, Ng A, Cao Z, Kuballa P, Daly MJ, Podolsky DK, Xavier RJ. A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy. Journal of Immunology. 2009 Apr 15;182(8):4917-30.






			Ramnik Xavier, M.D., Ph.D 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 which 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. 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 patho-physiological 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 questions 1) what are the mechanisms by which autophagy regulates innate and adaptive immunity 2) the role of leucine rich repeat domains in sensing microbial effectors 3) how are innate immune pathways dysregulated in inflammatory bowel disease. The adaptive immunity program focuses elucidating signal transduction pathways coordinated by the CARMA and Dlg1 family of scaffold proteins. We hope to gain additional insights about the immune system in terms of the underlying interaction and regulatory networks that define functional modules at the host-microbe interface and tumor immunity. In addition the team of computational biologists and mathematicians in the group are developing new algorithms to generate testable hypotheses and models using information from genome-wide studies, high-throughput screens and functional perturbation studies to gain insights into molecular and regulatory mechanisms in immunity and autoimmune disorders. Functional analysis of novel IBD loci/genes Crohn's disease (CD) and ulcerative colitis (UC) are idiopathic inflammatory disorders of the gastrointestinal tract known as the inflammatory bowel diseases (IBD). There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to disease. Ongoing collaborative studies with NIDDK Genetics Consortium have resulted in the discovery of novel IBD loci in Crohn's disease. We are currently developing molecular approaches (knock-out/knock-in mice, biochemistry, proteomics and computational approaches) to identify the functional implications of the novel regulatory and structural polymorphisms discovered in IBD. We are also interested in the development of network construction algorithms which integrate into a Bayesian framework physical and genetic associations using clinical and genotype data from patients and multiple high-throughput datasets to extract static and dynamic features for predicting phenotypic effects of temporal gene perturbation in tissues and cell types relevant to the disease state. References: Krishnan MN, Ng A, Sukumaran B, Gilfoy FD, Uchil PD, Sultana H, Brass AL, Adametz R, Tsui M, Qian F, Montgomery RR, Lev S, Mason PW, Koski RA, Elledge SJ, Xavier RJ* Agaisse H, Fikrig E. Whole genome RNA interface screening for human genes involved in West Nile virus. Nature 2008 Sep 11;455(7210):242-5. (Co-senior author) McCarroll SA, Huett A, Kuballa P, Chilewski S, Landry A, Goyette P, Zody MC, Hall JL, Brant SR, Cho JH, Duerr R, Silverberg MS, Taylor KD, Rioux J, Altshuler DM, Daly MJ, Xavier RJ. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genetics 2008 Aug 24; Epub ahead of print. Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ. Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant. PLos ONE 2008;3(10):e3991. Hitomi J, Christofferson DE, Ng A, Jianhua Y, Degterev A, Xavier RJ, Yuan J. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway by a genome wide siRNA screen. Cell 2008; Dec 26;135(7):1311-1323. Huett A, Ng A, Cao Z, Kuballa P, Daly MJ, Podolsky DK, Xavier RJ**. A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy. Journal of Immunology. 2009 Apr 15;182(8):4917-30.