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Smoking increases the risk of cardiac disease, heart rhythm disturbances (arrhythmias) and sudden cardiac death. Our goal is to advance early diagnosis and identify causes of cardiac disease, arrhythmias and death in the smoker’s heart by studying an inherited form of heart disease that causes lethal arrhythmias and sudden death called arrhythmogenic right ventricular cardiomyopathy (ARVC) as there are close parallels in the stress pathways that trigger the onset of disease in the ARVC and smoker’s heart. A key structure that shields heart muscle cells from stress are desmosomes, which mechanically tether heart muscle cells together at cell-cell junctions, especially during stress. Their importance in arrhythmias, cardiac disease and sudden cardiac death is critical as genetic mistakes in the DNA that encodes desmosomal cell-cell junction proteins, ultimately leads to breakdown of these cell junction structures resulting in ARVC. Thus, identifying key mechanisms that control desmosomal cell junction protein levels (assembly and breakdown) provides a novel entry point to identify therapeutic targets and key mechanisms that precipitate into arrhythmias, cardiac disease and sudden cardiac death (encompasses ARVC), that are also precipitated by smoking.
Using a combination of biochemistry studies and further analyzing hearts from our novel genetic mouse model of ARVC as well as human heart tissue and model systems of ARVC, we have extensive data that has uncovered a direct and early role for a gene called, COP9 signalosome subunit 6 (CSN6), in desmosomal cell junction protein levels in cardiac muscle that provides a new pathway to uncover early mechanisms that precipitate into cardiac arrhythmias, disease and sudden death. Our hypothesis is that CSN6 maintains desmosomal protein levels in cardiac muscle by controlling their degradation/breakdown. Thus, loss of CSN6 will dysregulate these degradation/breakdown pathways triggering loss of desmosomal protein levels, resulting in cardiac arrhythmias, disease and death, which encompass disease events associated with the ARVC and smoker’s heart. To test our hypotheses, we will determine the direct effects of CSN6 loss in cardiac muscle in mice (cardiac-muscle specific CSN6 knockout mouse model) and effects of therapeutic restoration of CSN6 pathways in unique cardiac arrhythmia model systems and assays that we have established in our laboratory.
Our studies will provide new insights into the mechanisms controlling desmosomal cell junction protein assembly/breakdown in cardiac muscle, while uncovering its relevance as a cause for the disease events encompassing ARVC (arrhythmias, cardiac disease, sudden death), which are directly relevant to the smoker’s heart. Based on our studies, we hope to impact new directions to develop early diagnostic markers, treatment avenues and therapeutic targets for cardiac arrhythmias, disease and sudden death, to help improve long-term clinical outcomes of people harboring smoking-related cardiac diseases.
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