TEXT: Approximately 5.7 million adult Americans have heart failure and this prevalence is projected to increase 25% by 2030. Despite improvement in heart failure treatment, including device therapy and cardiac transplantation, the mortality rate remains high. Cardiac arrhythmia is among the most common cause of mortality in heart failure patients. We and others have demonstrated the roles of mitochondrial dysfunction in heart failure due to various etiologies. Among these, mitochondrial cardiomyopathy demonstrates the most severe impairment of mitochondrial function. Mitochondrial disease is a group of rare genetic disorder due to mutation of mitochondrial proteins, most encoded by nuclear DNA and a few by mitochondrial DNA. Although only approximately 40% of patients with mitochondrial disease exhibit cardiac involvement, the presence of cardiomyopathy significantly predicts poor outcome and to date there is no effective therapy. Novel therapeutics is urgently needed to treat such patients. This study proposes manipulation of energy sensor signaling to enhance mitochondrial function, in order to treat mitochondrial disease, focusing on mitochondrial cardiomyopathy. Our preliminary data and previous publications suggest that energy sensor signaling, including AMP-activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+), play an important role to maintain mitochondrial function in mitochondrial disease as well as during development of heart failure. This study proposes strategies of manipulating energy sensor signaling (AMPK, NAD+, sirtuin) to improve mitochondrial function and to rescue cardiac arrhythmia in a mouse model of complex I deficiency with mitochondrial cardiomyopathy (Aim 1). To better recapitulate human disease, I propose to model human mitochondrial cardiomyopathy on a dish, using human induced pluripotent cell derived cardiomyocytes with mitochondrial complex I deficiency (Aim 2) and use the same strategies to rescue arrhythmia and cardiomyocyte dysfunction. The training award provides an excellent opportunity to learn novel technology of iPS, gene editing (such as CRISPR/cas), measurement of biomechanics and electrophysiology of cardiomyocytes as functional parameter of ?disease in a dish?, and extend my training in mitochondrial biology. This proposal is significant because it advances our scientific understanding of the relationship of mitochondrial dysfunction and heart failure and arrhythmia and test the method to rescue mitochondrial disease. Completion of this study may lead to development of novel therapy for untreatable mitochondrial disease. Finally, since mitochondrial dysfunction is evident in various etiologies of end-stage heart failure, the mitochondrial protective strategies proposed in this study may also be beneficial in other types of heart diseases.

Public Health Relevance

Heart failure is prevalent and imposes huge economic burden to our society. Cardiomyopathies are common disorders leading to significant morbidity and mortality and most have no effective therapies. In this proposal, we investigate the mitochondrial cardiomyopathy using mouse model of complex I deficiency and human induced pluripotent stem cell derived cardiomyocytes (disease in a dish model) to identify novel therapeutic targets for cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL145138-01
Application #
9646479
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Wang, Wayne C
Project Start
2019-02-01
Project End
2023-12-31
Budget Start
2019-02-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242