Muscle cells are unique in their ability to generate large amounts of force in a short period of time. In skeletal, cardiac and smooth muscle cells the method by which force is generated, the time scale required, and the mechanism for regulation are similar but yet unique. The differences within and between these tissues allow them to maximally perform their required functions.
One of the many differences between the muscle types are the contractile proteins themselves--the proteins directly involved in force generation. The major contractile proteins, actin and myosin, show tissue-specific types. These isoforms allow optimization of each muscle type for its specific function, including variation in speed of shortening, amount of force generated, and energy consumption. Differences in numerous other proteins within these cells, as well as their anatomical organization, regulatory mechanisms, innervation, etc., all contribute to the diversity between these tissues.
Research work in this lab involves the study of contractile, regulatory and cytoskeletal proteins in muscle including their expression, regulation and function in SM contraction. Molecular, mechanical, biochemical, histochemical, and immunological approaches are used to further our understanding of the function and regulation of these proteins and their isoforms.
In addition to this work I collaborate with Dr. John LaDisa in the Biomedical Engineering Department on Coarctation of the aorta (CoA). CoA is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA have improved life expectancy. However, these individuals still suffer a reduced average lifespan and morbidity resulting from cardiovascular disease, mostly due to hypertension. Identifying the mechanisms of morbidity is problematic in humans due to confounding variables such as differences in age at repair, time between correction and follow-up, severity of CoA before correction, and concurrent anomalies (e.g. bicuspid aortic valves or septal defects). To address this question, we developed a novel animal model that allows us to study CoA independent of these factors. This model replicates aortic changes in humans, and mimics correction at various durations using dissolvable suture. Our results to date using a putative clinical treatment guideline (20 mmHg pressure gradient) have revealed increased medial wall thickness and stiffening, a phenotypic shift in smooth muscle cells to the de-differentiated state, and endothelial dysfunction (decreased nitric oxide relaxation) all of which persist after correction. Microarray analysis of the aorta exposed to hypertension during the coarctation period revealed differentially expressed genes (DEG) in pathways unique to CoA and Corrected groups. These DEG include those associated with excitation contraction coupling that explain our findings, as well as unanticipated metabolic pathway genes, and have elucidated therapeutic options not previously considered for CoA patients.
Based on these findings, we hypothesize that the extent of vascular remodeling and endothelial dysfunction after Correction of CoA results from the severity of adverse hemodynamics caused by the coarctation, and can be mitigated by more discerning treatment guidelines or pharmacologically targeting DEG.