Christopher Mack

PhD, School of Medicine, UNC-Chapel Hill, Cancer Cell Biology

Christopher Mack

School of Medicine
UNC-Chapel Hill
Cancer Cell Biology

501 Brinkhous-Bullitt

Area of interest

Although we are interested in many areas of cardiovascular physiology and pathophysiology, the main focus of the laboratory is on the regulation of smooth muscle cell (SMC) growth and differentiation. SMC differentiation is very important during the formation of the vasculature, and alterations in the differentiation state of SMC have been shown to contribute to the development of atherosclerosis and hypertension. Therefore, it will be critical to identify the mechanisms that regulate this process.

We use a large number of molecular and genetic approaches to study SMC differentiation, and our major goals are to identifying the following:

1) the transcriptional mechanisms that regulate SMC differentiation marker gene expression. We and others have shown that serum response factor (SRF) and the myocardin family of SRF co-factors are critical regulators of SMC-specific transcription. A major goal is to identify the molecular mechanisms that regulate these factors in SMC. We have recently shown that the myocardin factors influence chromatin structure at the SMC-specific promoters by recruiting histone modifying enzymes and that the nuclear/cytoplasmic trafficking of the myocardin-related transcription factors (MRTFs) is critical for the regulation of SMC differentiation.

2) the intracellular signaling pathways by which environmental cues regulate SMC differentiation. A complex array of local environmental cues including growth factors, cell-cell and cell-matrix interactions, inflammatory stimuli, and mechanical stresses regulate SMC differentiation, but the precise cell signaling mechanisms involved are unclear. Our early work was instrumental in demonstrating that the small GTPase, RhoA, plays an important role in regulating SMC differentiation. We went on to show that the diaphanous-related formins (DRFs), a family of actin polymerizing proteins, are particularly important, and a major focus is on the mechanisms by which RhoA activates these proteins in SMC. We are also studying the signaling proteins that regulate RhoA activity in SMC including the RGS family of RhoGEFs that are activated by G-protein-coupled receptors. Finally, we are using genetically modified mice to examine RhoA signaling during vascular development and during the progression of vascular disease.

My lab also has an ongoing collaboration with Dr. Joan Taylor (UNC Dept of Pathology) to study the role of extracellular matrix signaling on SMC differentiation. Interestingly, SMC in the vasculature express high levels of a protein called FRNK (FAK-Related Non-Kinase) that acts an endogenous inhibitor of focal adhesion kinase (FAK). We have shown that FRNK expression is regulated during embryonic development and following vessel injury and inhibits SMC growth and migration. We are currently trying to delineate FRNK's role in SMC in vivo using a variety of genetically modified mouse models.

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