Jean E. Schaffer, M.D.

Professor
Internal Medicine
Cardiology
Developmental Biology

Molecular Cell Biology Program
Biochemistry Program

  • 314-362-8717

  • 314-362-8937

  • 314-747-0264

  • 8086

  • BJC-IH 10401

  • jschaff@wustl.edu

  • http://schafferlab.wustl.edu/

  • metabolism, RNA, cell death, diabetes, heart disease

  • Cellular responses to metabolic stress

Research Abstract:

The worldwide epidemic of diabetes poses a formidable challenge, because serious complications of this disease affect nearly every organ system. Diabetic complications stem from the underlying systemic metabolic abnormalities in this disease, which include both hyperglycemia and hyperlipidemia. Major goals of the Schaffer lab are to characterize the fundamental mechanisms through which excess metabolites cause cell damage and to understand how this process contributes to complications in metabolic disease.

Through genetic screens, we have discovered that small nucleolar RNAs (snoRNAs), a class of non-coding RNAs, play a critical functions in the response to metabolic stress. Our studies suggest new non-canonical functions for snoRNAs in which they target mRNAs for modifications that alter translation potential. Additionally, our finding that a lysosomal RNAse, RNASET2, is another key gene in this pathway, implicates regulated degradation of RNAs in metabolic stress responses.

Studies in the Schaffer laboratory are utilizing RNA affinity purification (RAP), cross-linking/immunoprecipitation (CLIP), and ribosome profiling, all coupled with RNAseq analysis to elucidate the mechanisms of action of snoRNAs and RNASET2. We have generated new mouse models with snoRNA loss-of-function to delineate the contributions of the snoRNAs to metabolic physiology. Furthermore, we are exploring the links between genetic variation in snoRNAs in humans and susceptibility to metabolic disease. In addition, we are also characterizing the contributions of additional genes identified in our original genetic screens.

Selected Publications:

Lee J, Harris AN, Holley CL, Mahadevan J, Pyles KD, Lavagnino Z, Scherer DE, Fujiwara H, Sidhu R, Zhang J, Huang SCC, Piston DW, Remedi MS, Urano F, Ory DS, Schaffer JE. Rpl13a small nucleolar RNAs regulate systemic glucose metabolism. J Clin Invest 2016, in press

Caputa G, Zhao S, Guerrero AE, Ory DS, Duncan JG, Schaffer JE. RNASET2 is required for oxidative stress-mediated cell death. Cell Death & Differentiation, 2015, 23:347-357. PMCID: PMC4716297

Jinn S, Brandis KA, Ren, A, Chacko A, Dudley-Rucker N, Fujiwara H, Jiang H, Olsen BN, Schaffer JE, and Ory DS. snoRNA U17 regulates cellular cholesterol trafficking. Cell Metab 2015, 21: 855-867. PMCID: PMC4456254

Holley CL, Li MW, Scruggs BS, Matkovich SJ, Ory DS, Schaffer JE. Cytoplasmic snoRNAs are dynamically regulated by NADPH oxidase. J Biol Chem 2015, 290: 11741-11748. PMCID: PMC4416874

Schilling J, Machkovech H, Kim AHJ, Schwendener R, Schaffer JE. Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol 2012, 303: H1366-H1373. PMCID: PMC3532539

Scruggs BS, Michel CI, Ory DS, Schaffer JE. SmD3 regulates intronic non-coding RNA biogenesis. Mol Cell Biol, 2012, 32: 4092-4103. PMCID: PMC3457340

Michel CI, Holley, CL, Scruggs BS, Sidhu, R, Brookheart RT, Listenberger LL, Behlke M, Ory DS, Schaffer JE. Small nucleolar RNAs, U32, U33, and U35 are critical mediators of metabolic stress. Cell Metab 2011, 14: 33-44. PMCID: PMC3138526

Borradaile NM, Buhman KK, Listenberger LL, Magee CJ, Morimoto TA, Ory DS, Schaffer JE. A critical role for eukaryotic elongation factor 1A-1 in lipotoxic cell death. Mol Biol Cell 2006 17:770-778.

Listenberger LL, Han X, Lewis SL, Cases S, Farese RV, Ory DS, Schaffer JE. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 2003 100:3077-3082.

Chiu H-C, Kovacs A, Ford DA, Hsu F-F, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 2001 107:813-822.

Last Updated: 10/24/2016 9:47:33 AM

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