Intercellular junctions are critical to the structure and function of cardiac tissue. Desmosomal molecules are a significant component of the cardiac intercalated disc and confer adhesive strength to cardiac cell-cell contacts. The importance of desmosomes to cardiac function is highlighted by studies of diseases such as arrhythmogenic cardiomyopathy (AC) and Carvajal syndrome. AC has been dubbed a "disease of the desmosome" due to its association with desmosome mutations and is characterized by fibro-fatty replacement of cardiac tissue leading to arrhythmia and sudden cardiac death. Carvajal syndrome is a cardiocutaneous disease characterized by dilated cardiomyopathy, woolly hair and palmoplantar keratoderma. I have identified a novel interaction between the desmosomal protein, desmoplakin (DP) and the RhoGEF Ect2, an upstream activator of Rho signaling. Several studies have suggested that electrophysiological manifestations of AC develop prior to detectable structural changes and that DP is involved in this process although the mechanism by which it is involved is unknown. Similar observations have also been made in Carvajal syndrome patients. I have found that DP is playing a role in the regulation of Ect2 localization and that Ect2 is required for the proper expression and localization of the gap junction protein Connexin 43 (Cx43). I hypothesize that DP acts as a scaffold in the cardiac area composita in order to localize and harness Rho GTPase signaling via the RhoGEF Ect2. I propose that this regulation is required for the expression and localization of the gap junction protein Cx43 in cardiac cells. I propose to elucidate the role that DP is playing in the regulation of Rho signaling in cardiac cells as well as determine the relevance of the DP-Ect2 interaction in disease models by analyzing the effect of site-specific mutations in DP on Ect2 binding. I will then determine the mechanism by which Ect2 is able to modulate Cx43 expression and if it is via the SRF transcriptional pathway. To study how the interaction contributes to cell function, I will then determine the extent to which expression of these mutations affects gap junction assembly and conductivity. Not only does this research define a novel interaction between DP and Ect2, it also promises to shed light on a previously unknown mechanism by which AC and Carvajal syndrome mutations in DP lead to arrythmia.
|Effective start/end date||7/1/15 → 6/30/17|
- American Heart Association Midwest Affiliate (15PRE25560138)