Monday, May 12, 2025
5/12/2025
Calcium Driven Fibroblast Dysregulation in Human Atrial Profibrotic Remodeling - PROJECT SUMMARY: Atrial fibrillation (AF) is the most common cardiac arrhythmia (affecting ~1-2% of the general population), resulting in markedly reduced quality of life and increased mortality, due to a combination of altered hemodynamics, progressive atrial and ventricular dysfunction, and embolic stroke. Limitations in current therapy allow AF paroxysms to progress to persistent forms of AF, as a result of extensive atrial structural and electrical changes that facilitate AF maintenance (“AF begets AF”). Myocardial remodeling, particularly atrial fibrosis, is a prominent feature of AF and contributes importantly to the vulnerable substrate promoting and stabilizing the arrhythmia. From a therapeutic perspective, the time course of fibrotic development is likely to define a window early in disease in which anti-arrhythmic pharmacotherapy can terminate AF and slow disease progression, before losing efficacy in grossly remodeled tissue. Therefore, therapies targeting the structural maladaptation, particularly fibrosis, could constitute novel antiarrhythmic strategies. Ca2+ dysregulation is broadly recognized as a critical element in AF pathophysiology, and Ca2+- dependent processes, both in atrial myocytes and fibroblasts, are thought to play an important role in AF- associated structural remodeling. However, while fibroblast Ca2+ homeostasis has been clearly linked to fibrotic outcomes, the mechanisms by which Ca2+ contributes to atrial fibroblast proliferation, differentiation, and transcription of extracellular proteins remain largely unknown, particularly in human fibroblasts and during AF. The overarching goals of this proposal are to investigate the basic molecular and cellular mechanisms of human atrial fibroblast calcium homeostasis and to study their derangements in AF promoting atrial fibrosis. Our approach will involve direct measurements of the major ion channels and molecular regulators of cytosolic Ca2+ in human atrial fibroblasts, which will then be combined in mathematical models defining mechanisms of Ca2+ entry, intracellular release and removal, and downstream fibrotic signaling. Together, these objectives will establish a multiscale mechanistic platform for understanding the precise role of Ca2+ in the human atrial fibroblast phenotypes that underlie remodeling of atrial myocardium in AF. We contend that these quantitative frameworks will provide new mechanistic insights into atrial fibrogenesis in AF, potentially serving as platforms for identifying new therapeutic targets. Each aim includes rigorously generated and validated modeling frameworks, informed by novel experiments in human atrial fibroblasts, and testing of specific hypotheses. Models and data will be distributed freely and widely via software and database infrastructure supported by Dr. Grandi's lab and scientific networking sites.
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