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Scripps Research Joint Appointments

Department of Cell and Molecular Biology
Faculty, Kellogg School of Science and Technology

Research Focus

Organisms go through cycles of metabolic activity, driven by internal cues (circadian, circannual clocks) and physiologic/behavioral inputs (e.g. feeding/fasting, physical activity/rest). In addition, organisms face environmental challenges (physical, chemical or psychological stressors) that require continual adaptation of the pathways regulating metabolism. The long-term goal of the lab is to understand how a network of transcriptional regulators integrates information from signals of metabolic challenges and needs (e.g. nutritional state, physical exercise), and relays them to changes in gene expression programs that enable adaptation.

The transcriptional network we study consists of the coactivators PGC-1α and PGC-1β, and the orphan nuclear receptors ERRα, ERRβ and ERRγ. PGC-1α and PGC-1β sense a range of metabolic signals and co-ordinate, in a tissue- and signal-specific manner, gene expression programs that regulate mitochondrial biogenesis, gluconeogenesis, and lipid metabolism. Studies in the last two years, including work from our lab, have shown that the effects of PGC-1α and PGC-1β on mitochondrial biogenesis are mediated to a large part by the orphan nuclear receptor ERRα. Current studies aim in understanding 1) the regulation of the PGC-1/ERR network, and 2) the spectrum of biological pathways controlled by PGC-1/ERRs, with an emphasis in adaptive responses in the neuromuscular system. Mitochondrial dysfunction has been implicated as an underlying cause of insulin resistance and diabetes, and muscle- and neuro-degenerative disease. Hence, studies of the PGC-1/ERR network are likely to shed light not only on the basic mechanisms that regulate adaptation to metabolic stressors, but also on the molecular pathogenesis and possible treatment of metabolic disease.

Education

B.S., Biology, University of Sussex, 1986
Ph.D., Molecular Biology, University of Pennsylvania, 1991

Professional Experience

1987 - 1991 Ph.D. thesis with Dr. R. Weinmann, University of Pennsylvania / Wistar Institute, Philadelphia, PA
1991 - 1997 Postdoctoral fellow with Dr. K. R. Yamamoto, University of California, San Francisco, CA
1997 - 2003 Junior group leader, Division of Biochemistry, Biozentrum of the Univ. of Basel, Switzerland
2003 - 2006 Assistant Professor, Department of Cell Biology, The Scripps Research Institute, CA

Selected References

Chang J.S., Huypens P., Zhang Y., Black C., Kralli A. and T.W. Gettys (2010). Regulation of NT-PGC-1α subcellular localization and function by PKA-dependent modulation of nuclear export by CRM1. J. Biol. Chem. 285, 18039-18050.

Hock M.B. and A. Kralli (2009). Transcriptional Control of Mitochondrial Biogenesis and Function. Annu. Rev. Physiol. 71, 177-203.

Villena J.A. and A. Kralli (2008). ERRα: a metabolic function for the oldest orphan. Trends Endocrinol. Metab. 19, 269-76.

Olson B.L., Hock M.B., Ekholm-Reed S., Wohlschlegel J.A., Dev K.K., Kralli A. and S.I. Reed (2008). SCFCdc4 Acts Antagonistically to the PGC-1α Transcriptional Coactivator by Targeting It for Ubiquitin-Mediated Proteolysis. Genes Dev. 22, 252-64.

Villena J.A., Hock M.B., Chang W.Y., Barcas J.E., Giguère V. and A. Kralli (2007). Orphan nuclear receptor ERRα is essential for adaptive thermogenesis. Proc. Natl. Acad. Sci. USA 104, 1418-1423.

Herzog B., Cardenas J., Hall R.K., Villena J.A., Budge P.J., Giguere V., Granner D.K., and A. Kralli (2006). Estrogen-related receptor α is a repressor of Phosphoenolpyruvate Carboxykinase gene transcription. J. Biol. Chem. 281, 99-106.

Teyssier C., Ma H., Emter R., Kralli A., and M.R. Stallcup (2005). Activation of Nuclear Receptor Coactivator PGC-1α by Arginine Methylation. Genes Dev. 19, 1466-73.

Schreiber S.N., Emter R., Hock M.B., Knutti D., Cardenas J., Podvinec M., Oakeley E.J. and A. Kralli (2004). The estrogen-related receptor α (ERRα) functions in PPAR γ coactivator 1α (PGC-1α-induced mitochondrial biogenesis. Proc. Natl. Acad. Sci. USA 101, 6472-6477.