Laura Weise-CrossBachelor of Science in Biochemistry and Bachelor of Arts in the Plan II Honors Program from the University of Texas
Dissertation Project: RhoA Signaling through the Diaphanous-Related-Formins in Smooth Muscle Cell Differentiation
During vasculogenesis or angiogenesis, the investment of newly developing vessels with a layer of differentiated smooth muscle cells (SMC) is a necessary step in vessel maturation. Differentiated, contractile cells provide structural support but also regulate vessel diameter to control blood flow and blood pressure. It is clear that alterations in SMC function contribute to cardiovascular diseases. Under pathologic conditions such as atherosclerosis, SMC can change to a more proliferative, migratory, and synthetic phenotype. While SMC within the intima help stabilize injured vessels, they also contribute to plaque growth and lumen narrowing. Aberrant SMC contractility also contributes to the development of hypertension, and a large number of pharmacologic interventions have been developed that target this SMC function. Finally, since the presence of SMC often stabilizes endothelial cell function, it is likely that SMC play a role during pathologic angiogenesis (i.e. tumor growth and diabetic retinopathy). Thus, identifying the molecular mechanisms that regulate SMC differentiation, proliferation, and migration will have important implications for understanding normal and pathologic cardiovascular function.
The Mack lab has previously shown that RhoA signaling plays a major role in the regulation of SMC phenotype by regulating the nuclear localization of the myocardin-related transcription factors (MRTFs). RhoA also controls SMC contractility by regulating myosin phosphorylation and is important for the cytoskeletal changes that are required for cell migration. The overall goal of my thesis project is to identify novel signaling mechanisms in this pathway and to evaluate RhoA's contribution to SMC differentiation in vivo. I am studying the effects of nuclear RhoA signaling on SMC differentiation marker gene expression with a major focus on the role of actin polymerization on nuclear structure, MRTF localization, and transcriptional activation. I am also investigating the effects of the RhoA effector, mDia, on SMC differentiation in vivo through various mouse models.
I came to UNC in the fall of 2009 through the Biological and Biomedical Sciences Program (BBSP). I did my first rotation in Christopher Mack’s lab, studying the role of the constitutively active Rho-family G-proteins, Rnd1 and Rnd3, on RhoA signaling in SMCs. My second rotation was with Ellie Tzima, where I analyzed the downstream effects of knocking down the adaptor protein Shc in endothelial cells in the presence and absence of VEGF stimulation. I completed my third rotation with Jay Brenman, where I did cell culture studies to assess the activities of the cellular energy sensor AMPK as a potential target for gliomas.