Junctophilin 2 (JP2) is a structural protein required for the formation of junctional couplings (i.e., cardiac dyads) between transverse (T)-tubule membrane and sarcoplasmic reticulum (SR) and is fundamental for local control of Ca2+-induced Ca2+ release and efficient contraction in ventricular myocytes during cardiac excitation- contraction (E-C) coupling. In animal models of heart failure, JP2 protein levels progressively decline, leading to T-tubule remodeling and loss of E-C coupling function. JP2 levels are also markedly reduced in human failing hearts. Our recently published and preliminary data demonstrate that JP2 is posttranslational regulated by calpain, a Ca2+-activated protease implicated in a variety of heart diseases. JP2 cleavage by calpain was originally hypothesized to underlie JP2 downregulation in failing hearts. In pilot studies, we made the novel and unexpected observation that an N-terminal JP2 cleavage fragment, termed JP2NT, unlike full length JP2, is imported into nucleus, where it has a profound function in transcriptional reprogramming in cardiomyocytes. However, the (patho) physiological consequences of JP2NT nuclear localization and related molecular mechanisms are completely unknown. Based on these novel exciting preliminary findings, we hypothesize that, in response to stress, calpain-mediated cleavage of JP2 transforms JP2 from a structural protein into a transcriptional regulator that reprograms the transcriptional profile of damaged cardiomyocytes and represses the development of cardiac hypertrophy. This molecular event may be an important trigger for transcriptional remodeling, serving as an unappreciated protective mechanism under pathological conditions. We will test our hypothesis using a multidisciplinary approach, including multiple novels transgenic and CRISPR-based mouse models, molecular biology, biochemistry and a novel in situ confocal imaging technique developed by our lab.
In Aim 1, we will explore the molecular mechanisms underlying JP2NT transcriptional regulation in cardiomyocytes, whereas Aim 2 will examine the patho(physiological) consequences of JP2NT in the heart. We anticipate the proposed studies will provide significant insights into the novel functions of JP2NT in membrane-to-nucleus signal transduction in the setting of cardiac stress and new insights into the cross- communication between cardiomyocyte structural remodeling and transcriptional remodeling in heart disease. This information will serve as a platform for the future development of novel heart failure therapeutics.
Heart failure is the most common cause of hospitalization in patients over 65 and causes an enormous burden on our health care system. New therapeutic approaches for heart failure are still critically needed. Our studies will likely reveal novel insihts into the function of the truncated form of structural protein Junctophilin-2 in heart failure, and shed light on future development of novel heart failure therapeutics.
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