Faculty

Anastasia Kralli 
Associate Professor
CHEMICAL PHYSIOLOGY
TSRI - 2003

Education 
B.Sc., University of Sussex, England, 1986

Ph. D., University of Pennsylvania, Philadelphia, 1991

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.

Selected References 
Schreiber S.N., Knutti D., Brogli K., Uhlmann T. and A. Kralli (2003). The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor a (ERRa). J. Biol. Chem. 278, 9013-9018.

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.

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.

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.