Wednesday, February 5, 2025
2/5/2025
PROJECT ABSTRACT Atrial fibrillation (AF) is the most common sustained arrhythmia that is estimated to affect over 40 million people worldwide. Increases in atrial electrophysiological (action potential duration dispersion, altered conduction velocity) and structural heterogeneity (fibrosis, scarring) can increase the risk for AF. The cause for AF is unknown, but a variety of factors such as genetic predisposition, age, cardiovascular co-morbidities, inflammatory diseases can increase its risk. Ulcerative colitis (UC), a subtype of inflammatory bowel disease, was recently shown to increase a patient’s risk for AF. UC is an intestinal inflammation within the colon and rectum of the gastrointestinal tract (GIT) that promotes gut dysbiosis. Patients with active colitis have a two-fold increased risk for AF, and even in remission exhibit changes in atrial excitation and contraction that show atrial remodeling. Yet, the mechanism with which UC increases the risk for AF remains undetermined and is the focus of my project. Preliminary data in a mouse model of active colitis show an attenuated vagal tone, increased sensitivity of the muscarinic acetylcholine receptor M2 (M2R) to cholinergic signaling, and prolonged atrial conduction. These changes are reversible during remission, but in the chronic colitis model are maintained along with a reduction in the heart/atrial weight, atrial myocyte size and electrophysiological and structural remodeling of the atria. Based on my pilot data I propose to test the overall hypothesis that UC-induced dysregulation of vagal nerve activity increases the risk for AF during UC disease progression. To test this hypothesis, I will use a mouse model of active and chronic colitis. Aim 1 will examine the mechanism by which the risk for atrial arrhythmic activity is increased during active colitis. In a mouse model of active colitis, I will determine if AF occurrence is a consequence of a dysregulation in vagal signaling, promoting electrophysiological heterogeneity. Aim 2 will determine the mechanism by which UC induces an exaggerated response of the heart to cholinergic signaling. I will examine if a UC-induced attenuated vagal tone promotes an upregulation of atrial cardiomyocyte M2R expression. Aim 3 will examine the mechanism by which the risk for atrial arrhythmic activity is increased during chronic colitis. In a mouse model of chronic colitis, I will determine if AF occurrence is a consequence of an increase in structural heterogeneity. The proposed work will elucidate a mechanism in which AF risk is increased during UC disease progression. Successful completion of the proposed research would provide an understanding of the interplay between the heart, GIT and ANS, and allow for a one possible mechanism of AF to be determined. The findings will lay the groundwork for the creation of a translational treatment for one of the diseases associated with UC. The research project will be guided by an exceptional team of sponsors that are well-suited to provide the proper training of the techniques needed to complete the research, mentorship, and to ensure short-term and long-term success of the trainee. The proposed work will also promote my ability to execute a scientific project and development as an independent scientist.
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