Research Interests:

I. Molecular and Cellular Mechanism of Myofibroblast Differentiation

In my work, I am interested in understanding the molecular and cellular characteristics of myofibroblasts and determining the intracellular mechanisms responsible for their growth and function. Myofibroblasts are unique mesenchymal cells from a variety of organ systems that are involved in normal tissue development, remodeling and repair. Their recruitment during inflammation is accompanied by a transition from a quiescent to an activated state in response to various cytokines and growth factors. This activated state of the myofibroblast is characterized by an increase in a -smooth muscle actin expression, extracellular matrix (ECM) protein expression, proliferation, and contractility. During injury however, the continued and unchecked proliferation of these cells has implicated them in several disease states including pulmonary fibrosis and lymphangioleiomyomatosis (LAM). LAM is a rare but devastating lung disease in young women characterized by the abnormal proliferation of “LAM cells” which share many common features with myofibroblasts. Ultimately, I am interested in understanding how myofibroblasts contribute to the pathogenesis of LAM and other interstitial diseases.

II. Genetic Regulation of Phosphorylase-b Kinase Expression

A second area of research involves understanding the transcriptional regulation of the complex oligomeric enzyme phosphorylase b kinase (PhK). PhK, the first kinase discovered, is a regulatory enzyme involved in the cascade activation of glycogenolysis. In liver, these reactions allow for the maintenance of blood glucose, and in muscle, they lead to energy production to sustain contraction. PhK is the largest and most complex protein kinase known. It is a hexadecamer of four copies of four different subunits with a stoichiometry of (abgd)4 and total mass of 1.3 x 106 Da. While much work has been done on elucidating the catalytic mechanism and structural organization of this protein, understanding its genetic regulation has lagged significantly. In my lab we are focused on determining those mechanisms that function in complex coordination of PhK transcription by studying the promoter region for each PhK gene and elucidating those cis- and trans-acting elements responsible for regulating gene expression. Such information will provide tremendous insights into understanding how the precise temporal and spatial expression (muscle vs. liver vs. heart) of PhK is coordinated. Furthermore, an analysis of the sequence variation in PhK promoter regions among species will aid in understanding how evolutionary adaptations in these genes have led to alterations in gene expression and function.

Recent Publications

1. Rice, N.A., Widegren, U., Holton, L.E., Allen, D.L., and Leinwand, L.A. Regulation of
skeletal myosin gene expression in myofibroblasts by members of the MAPK pathway.
In preparation.

2. Rice, N.A. and Leinwand, L.A. (2003) Skeletal muscle myosin heavy chain is a unique
marker and essential activator of pulmonary myofibroblast function. J. Cell. Biol. Submitted.

3. Andreeva, I.E., Rice N. A., and Carlson, G.M. (2002) The regulatory a subunit of
phosphorylase kinase may directly participate in the binding of glycogen phosphorylase.
Biochemistry (Moscow) 67, 1197-1202.

4. Rice, N.A., Nadeau, O.W., Yang, Q. and Carlson, G.M. (2002) The calmodulin-binding domain of the catalytic gamma subunit of phosphorylase kinase interacts with its inhibitory alpha subunit: Evidence for a Ca2+-sensitive network of quaternary interactions. J. Biol. Chem. 277, 14681-14687.

5. Rice, N.A. and Carlson, G.M. Phosphorylase kinase. Wiley Encyclopedia of Molecular Medicine. Vol. 4 John Wiley and Sons, Inc., New York, 2001, pp. 2487-2490.

6. *Ayers, N.A., Wilkinson, D.A., Fitzgerald, T.J. and Carlson, G.M. (1999) Self-association of the alpha subunit of phosphorylase kinase as determined by two-hybrid screening. J. Biol. Chem, 274, 35583-35590.

7. *Ayers, N.A., Nadeau, O.W., Read, M.W., Ray, P. and Carlson, G.M. (1998) Effector-sensitive crosslinking of phosphorylase-b kinase by the novel crosslinker 4-phenyl-1,2,4-triazoline-3,5-dione. Biochem. J. 331, 137-141.

8. *Ayers, N.A., Kapás, L. and Krueger, J.M. (1997) The inhibitory effects of Nw-nitro-L-arginine
methyl ester on nitric oxide synthase activity vary among brain regions in vivo but not in vitro. Neurochem. Res. 22, 81-86.

9. *Ayers, N.A., Kapás, L. and Krueger, J.M. (1996) Circadian variation of nitric oxide synthase activity and cytosolic protein levels in rat brain. Brain Res. 707, 127-130.

*maiden name