Tanner Reeb and Jessica Ponce to Present at Genetics Student Seminar on 2/20/17

Time heals all wounds, but not without IRF6 and ARHGAP29
T Reeb, M Dunnwald

Chronic wounds affect 6.5 million people in the US, yet little is known about the genetic and molecular mechanisms regulating wound healing. Wound closure requires the concerted action of cellular proliferation, differentiation, and migration. Interferon Regulatory Factor 6 (IRF6) has been shown to regulate all of these processes, with murine embryos deficient for Irf6 displaying impaired wound healing. Additionally, IRF6-deficient keratinocytes have been shown to display both a decrease in the expression of Rho GTPase Activating Protein 29 (ARHGAP29) as well as an increase in stress fibers. ARHGAP29 is a Rho GTPase Activating Protein with a high affinity for RhoA. RhoA is a Rho GTPase which has been shown to play key roles in wound healing and the regulation of stress fibers. However, despite all that we know about IRF6 and RHOA, little is known about how IRF6 regulates ARHGAP29 and the role of ARHGAP29 in cellular migration, cellular adhesion, and wound healing. We hypothesize that ARHGAP29 is transcriptionally regulated by IRF6 and functionally regulates Rho GTPases. Perturbing this system will result in impaired wound healing. We plan to test this hypothesis by performing full thickness excisional wounds on Arhgap29 mutant mice. To test whether Irf6 regulatesArhgap29, a rescue experiments will be performed to determine if overexpression of Arhgap29 can alleviate the phenotypes observed in Irf6-deficient keratinocytes. By further understanding the roles of IRF6 and ARHGAP29 in wound healing, it would provide positive impacts including the ability to predict wound healing complications, the generation of novel therapies as a means preventing such complications, the potential to gain insights into the role of ARHGAP29 and IRF6 in other disorders (such as cleft lip and palate), and ultimately, the improvement of patient outcomes.



 Ponce1,2, D. Hall2, I. Martin2, C. Grueter1,

Interdisciplinary Graduate Program in Genetics, Department of Internal Medicine, University of Iowa.

Cardiovascular disease is the leading cause of death worldwide. The damage inflicted on the myocardium during myocardial infarction (MI) results from (1) hypoxia during ischemia and (2) oxidative damage upon subsequent reperfusion. Despite extensive investigation, the pathophysiology of myocardial injury in response to ischemia is not fully understood. Cyclin C is a coactivator of the Mediator kinase subcomplex which regulates transcription of genes involved in cardiac metabolism, energy homeostasis and responsiveness of the heart to stress. Recent studies have shown Cyclin C to function independent of mediator in regulating stress-induced mitochondrial hyper-fission in yeast in response to oxidative damage. In humans, the constant electrical and mechanical activities of the heart require a continuous energy supply met by a rich stockpile of mitochondria. Additionally, mitochondrial dysfunction increases the pathogenesis in response to ischemia injury. Although studies have shown the effects of mitochondrial dysfunction in heart disease, there is a current gap in knowledge to understand the functional role of Cyclin C in cardiac mitochondria. We hypothesize that injury in response to IR depends on the translocation of Cylinc C from the nucleus to mitochondria where it regulates mitochondrial dynamics. Preliminary data demonstrates Cyclin C translocation in response to stress in cardiomyocytes isolated from adult mouse and neonatal rats. The overall goal of this project is to define the mechanisms whereby Cyclin C regulates metabolism, energy homeostasis in heart disease via two functions: regulating mitochondrial dynamics, as well as regulating transcription of crucial mitochondrial genes. These studies will provide new insights into the regulation of cardiac energy metabolism and may yield novel therapeutic strategies for modulating these processes in the settings of heart disease.


Posted on February 13, 2017, in Uncategorized. Bookmark the permalink. Leave a comment.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: