This proposal details a comprehensive 5-year training program for my career development in cardiovascular research. I have planned this mentored research program to provide the additional scientific training necessary for an independent career in academic research. I will gain in-depth experience in the areas of biochemistry, gene regulation, cellular electrophysiology, and in vivo physiology as applied to animal models of heart failure and arrhythmias. Dr. Steven Marx will by my primary mentor for scientific and career development. Dr. Marx is a leader in the field of cardiovascular ion channels. The project will be performed in collaboration with Dr. Ira Goldberg, an expert in lipids and myocardial metabolism. In addition, an advisory committee of established cardiovascular scientists (Drs. Andrew Marks, Robert Kass, and Fadi Akar) and an administrator (Dr. Jamie Rubin) will provide scientific and career advice. The central hypothesis of this application is that increased cardiac myocyte lipid content leads to abnormal regulation of ion channels and gap junctions, promoting arrhythmia. Increased cardiac myocyte lipid stores are observed in obese and diabetic patients and this is proposed to contribute to the pathophysiology of heart failure, a syndrome termed lipotoxic cardiomyopathy. We have recently found that a mouse model of lipotoxic cardiomyopathy, a transgenic mouse with cardiac-specific over expression of PPAR3, has prolonged QRS and QT intervals, and dies suddenly at 2-8 months of age from ventricular tachycardia (VT). PPAR3 is a ligand-activated transcription factor that regulates lipid and glucose metabolism. These PPAR3 cardiac over expression mice gradually develop a dilated cardiomyopathy with impaired systolic function and have abnormal accumulation of intracellular lipids, but sudden death often occurs before HF develops. We have found that individual cardiac myocytes from these cells have prolonged action potential duration, probably from reduced potassium current. Further, connexin 43, the main component of the ventricular gap junction, is down regulated at the transcriptional level and the protein level, which is known to promote VT. This mouse is thus a unique model of an increasingly common form of human heart disease associated with diabetes and obesity, with a natural history that recapitulates a common cause of death in these patients.
My aims are: 1. To characterize the abnormal cellular electrophysiology leading to arrhythmias in lipotoxic cardiomyopathy 2. To characterize abnormal cardiac conduction in lipotoxic cardiomyopathy, and 3. To determine the molecular mechanisms of reduced connexin expression in lipotoxic cardiomyopathy.
Heart failure is one of the leading causes of morbidity and mortality in the USA. Sudden cardiac death is responsible for up to 50% of deaths among patients with HF and is often due to ventricular arrhythmias. Diabetes and obesity are associated with an increased risk of cardiomyopathy and heart failure. Increased cardiac myocyte lipid stores are observed in obese and diabetic patients and this is proposed to contribute to the pathophysiology of heart failure, a syndrome termed lipotoxic cardiomyopathy. This project seeks to understand the pathophysiology of lipotoxic cardiomyopathy that leads to arrhythmias and sudden death by using animal models.
|Joseph, Leroy C; Kokkinaki, Dimitra; Valenti, Mesele-Christina et al. (2017) Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function. JCI Insight 2:|
|Joseph, Leroy C; Barca, Emanuele; Subramanyam, Prakash et al. (2016) Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes. PLoS One 11:e0145750|
|Wan, Elaine; Abrams, Jeffrey; Weinberg, Richard L et al. (2016) Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice. J Clin Invest 126:112-22|
|Joseph, Leroy C; Subramanyam, Prakash; Radlicz, Christopher et al. (2016) Mitochondrial oxidative stress during cardiac lipid overload causes intracellular calcium leak and arrhythmia. Heart Rhythm 13:1699-706|
|Morrow, John P; Marx, Steven O (2015) Novel approaches to examine the regulation of voltage-gated calcium channels in the heart. Curr Mol Pharmacol 8:61-8|
|Shin, Ji-Yeon; Le Dour, Caroline; Sera, Fusako et al. (2014) Depletion of lamina-associated polypeptide 1 from cardiomyocytes causes cardiac dysfunction in mice. Nucleus 5:260-459|
|Huang, Haiyan; Joseph, Leroy C; Gurin, Michael I et al. (2014) Extracellular signal-regulated kinase activation during cardiac hypertrophy reduces sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) transcription. J Mol Cell Cardiol 75:58-63|
|Huang, Haiyan; Amin, Vaibhav; Gurin, Michael et al. (2013) Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels. J Mol Cell Cardiol 59:151-8|
|Yang, Lin; Katchman, Alexander; Samad, Tahmina et al. (2013) ?-adrenergic regulation of the L-type Ca2+ channel does not require phosphorylation of ?1C Ser1700. Circ Res 113:871-80|
|Choi, Jason C; Muchir, Antoine; Wu, Wei et al. (2012) Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Sci Transl Med 4:144ra102|
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