Over five million Americans have heart failure (HF), with more than 500,000 new cases added each year in what is a growing epidemic. Yet the pathophysiology of heart failure progression remains poorly understood and, as a result, our ability to make therapeutic decisions remains limited. Development of more specific and prognostic biomarkers that are directly tied to HF progression is required to improve clinical management. I have recently found that a key scaffolding protein, BIN1, is important to the pathogenesis of altered calcium handling in human HF. With this knowledge, my long term goal is to develop a novel HF biomarker of cardiac reserve through understanding the biology of BIN1 and calcium handling in normal and diseased cardiomyocytes. The objective of this particular application is to understand the role of BIN1 in regulation of the calcium transients in heart failure, and to use BIN1 to develop a diagnostic and prognostic test in HF patients. My central hypothesis is that BIN1 expression is reduced in failing human cardiomyocytes, and that BIN1 levels in tissue and serum correlate with recovery potential of myocardial tissue. The rationale is that successful completion of the proposed research will fill a gap in the knowledge of BIN1 based regulation of calcium transients in HF which helps to develop an innovative diagnostic and prognostic test of cardiac reserve in HF patients.
Specific Aim #1 is to identify the role of BIN1 in Cav1.2 trafficking and calcium transient regulation in failing human cardiomyocytes. Quantitative rtPCR, western blot, ELISA, immunofluorescence, and T-tubule fractionation will be used to assess the cellular expression and localization of BIN1 and Cav1.2 in failing and non-failing human cardiomyocytes. In adult mouse cardiomyocyte models, surface biotinylation and live-cell calcium imaging will be used to study Cav1.2 trafficking and calcium transients in BIN1 depleted cardiomyocytes.
Specific Aim #2 is to identify myocardial tissue BIN1 expression as a diagnostic and prognostic test of HF progression in end-stage human cardiomyopathy patients. Quantitative immunofluorescence will be used on heart biopsies to determine ventricular BIN1 expression level for analysis with clinical contractile parameters and outcome data.
Specific Aim #3 is to identify serum BIN1 as a novel prognostic HF biomarker of cardiac reserve in cardiomyopathy patients. Serum BIN1 will be measured by cardiac specific ELISA in a large population of cardiomyopathy patients from the UCSF heart failure clinic and an age-matched normal control population for analysis with clinical data. The contribution is expected to identify BIN1 as a HF mediator and biomarker to help track the progression of heart failure and prognosticate clinical outcomes. This contribution will be significant because such discovery will shift current paradigm in myocardial health assessment for monitoring disease progression and guiding therapeutic strategies in heart failure. The research proposed in this application is innovative because it focuses on a new diagnostic and prognostic test of HF, tissue and serum BIN1 level, which assess cardiac reserve through directly reflecting the biochemical health of individual cardiomyocytes.
The proposed research is relevant to public health because it opens a new understanding and ability to monitor heart failure progression which will substantially advance heart failure diagnosis and therapy. The project is relevant to NIH's mission because the introduced new paradigm of heart failure biomarkers of cardiac reserve will change the status quo by providing tools to aid specific diagnosis, prognosis, and individual treatment guidance in heart failure patients.
|Fu, Ying; Xiao, Shaohua; Hong, TingTing et al. (2015) Cytoskeleton regulation of ion channels. Circulation 131:689-91|
|Hong, TingTing; Yang, Huanghe; Zhang, Shan-Shan et al. (2014) Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat Med 20:624-32|
|Gao, Danchen; Zhang, Li; Dhillon, Ranvir et al. (2013) Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart. PLoS One 8:e60967|
|Hong, Ting-Ting; Cogswell, Rebecca; James, Cynthia A et al. (2012) Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm 9:961-7|
|Smyth, James W; Vogan, Jacob M; Buch, Pranali J et al. (2012) Actin cytoskeleton rest stops regulate anterograde traffic of connexin 43 vesicles to the plasma membrane. Circ Res 110:978-89|
|Hong, Ting-Ting; Smyth, James W; Chu, Kevin Y et al. (2012) BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes. Heart Rhythm 9:812-20|