Thursday, November 21, 2024
11/21/2024
ABSTRACT Myocardial infarction is the most common form of acute cardiac injury attributing to heart failure. While there have been significant advances in current therapies, mortality and morbidity remain high. In response to cardiac injury, macrophages are recruited in high numbers to the infarcted myocardium and act to control the initiation, maintenance, and resolution of the inflammatory response. Blood-derived and tissue-resident macrophages exhibit the unique characteristic to phenotypically switch between a pro-and anti-inflammatory phenotype producing a sequential spectrum of cytokines, chemokines, and growth factors exerting both pro-and anti- inflammatory effects. Despite this understanding, much remains to be learned about the plasticity of macrophages during tissue repair and the factors that regulate macrophage function. The regulatory potential of circular RNAs (circRNA) in cardiovascular disease has begun to garner interest as a largely unexplored topic. Circular RNAs are newly discovered non-coding RNA generated from protein-coding genes ubiquitously expressed in mammalian tissue, highly conserved among species, and recently implicated in the possible regulation of macrophage activation. However, there are currently no reports on the role of circRNAs in macrophage biology and function during cardiac ischemia. Our central hypothesis is that circRNA may modulate monocyte/macrophage biology during cardiac injury and therapeutically regulate post-injury cardiac inflammation. Preliminary data identified circRNAs differentially expressed in pro-and anti-inflammatory macrophages, including circRNA CDR1as (circ-CDR1as). This project aims to determine the specific role of circ- CDR1as in the promotion of monocyte/macrophage class switching and how circ-CDR1as modulates the functions of monocytes post-cardiac injury. Further, we plan to test the efficacy of circ-CDR1as for cardiac repair in vivo using a mouse MI model by loss/gain of function approaches. Lastly, investigate the mechanism by which circular circ-CDR1as invokes physiological changes in macrophages in both the steady-state and injured heart. Collectively, our goal is to identify and establish the role of circ-CDR1as as a potential therapeutic for the resolution of inflammation after cardiac injury to promote cardiac repair and remodeling.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
