The applicant, Hossein Ardehali, M.D., Ph.D., completed his residency and fellowship training at The Johns Hopkins Hospital in 2004 and has been an Assistant Professor of Medicine, Molecular Pharmacology and Biological Chemistry at Northwestern University since then. He just completed a K08 grant (funded in 2005 with a priority score of 120), and has an active R01 grant that was funded in 2007 with a score of 4th percentile. The candidate has a solid interest in pursuing basic science research along with patient care in an academic institution, and Northwestern has and will continue to provide an excellent supportive environment. Dr. Ardehali's long term goals are to become a successful investigator in the field of cardiobiology and to apply basic science discoveries to clinical practice with the hope of developing new treatments for ischemic heart disease. This proposal details Dr. Ardehali's research career development plan that integrates four objectives: 1) to attend scientific enrichment programs, 2) to establish distinct areas of research that builds upon his clinical and scientific strengths, 3) to improve the methodological capability of the lab, and 4) to cultivate collaboration with leading scientists in the field. The applicant's major focus is on functional characterization of a novel mitochondrial protein, mitochondrial ATP-binding cassette protein 1 (mABC1). The applicant had shown that overexpression of mABC1 leads to protection against cell death, but the primary function of the protein is not known. Recent results from the applicant's lab indicate that downregulation of mABC1 in isolated cardiomyocytes results in an increase in mitochondrial iron and a reduction in the activity of cytosolic iron-sulfur cluster (Fe/S) containing proteins. He has also generated cardiac specific mABC1 knockout (KO) and transgenic (TG) animals. Heart specific mABC1 KO results in mitochondrial iron accumulation and leads to the development of cardiomyopathy, while mABC1 TG mice are resistant to doxorubicin-induced cardiotoxicity and have lower mitochondrial iron levels. Together, these results suggest that mABC1 is involved in mitochondrial iron homeostasis and the transport of Fe/S clusters out of the mitochondria, and overexpression of the protein in the heart protects against doxorubicin induced cardiotoxicity. The central hypothesis of this proposal is that mABC1 is regulated by mTOR pathway and that the cardioprotective effects of mABC1 are through a reduction in autophagy and an improvement in mitochondrial biogenesis and function.
In Aim 1, the applicant will evaluate regulation of mABC1 by mTOR pathway.
In Aim 2, the effects of mABC1 modulation on cellular iron flux will be assessed, and Aim 3 will evaluate the mechanism for the cytoprotective effects of mABC1 by studying mitochondrial function and autophagy in response to mABC1 modulation. The proposed studies are logical and compelling sequence of experiments designed to follow up on our key observation that mABC1 is protective against cell death and plays a role in mitochondrial iron homeostasis and Fe/S cluster export out of mitochondria.

Public Health Relevance

Iron is a required component of heart cells and is essential for their baseline function. We have shown that a protein called mABC1 is protective against cardiac cell death and plays a role in regulating mitochondrial iron levels. Furthermore, mice that have high levels of mABC1 protein are protected against the toxic effects of the cancer drug doxorubicin. Here, we will study how mABC1 levels are regulated in the heart and will study the mechanism for its protective effects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Scientist Development Award - Research (K02)
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Special Emphasis Panel (ZHL1-CSR-K (F1))
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Carlson, Drew E
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Wu, Rongxue; Chang, Hsiang-Chun; Khechaduri, Arineh et al. (2014) Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy. J Clin Invest 124:4795-806
Ardehali, Hossein (2014) How to write a successful grant application and research paper. Circ Res 114:1231-4
Bayeva, Marina; Sawicki, Konrad Teodor; Butler, Javed et al. (2014) Molecular and cellular basis of viable dysfunctional myocardium. Circ Heart Fail 7:680-91
Ichikawa, Yoshihiko; Ghanefar, Mohsen; Bayeva, Marina et al. (2014) Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 124:617-30
Qiao, Aijun; Khechaduri, Arineh; Kannan Mutharasan, R et al. (2013) MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes. J Am Heart Assoc 2:e000121
Rines, Amy K; Ardehali, Hossein (2013) Transition metals and mitochondrial metabolism in the heart. J Mol Cell Cardiol 55:50-7
Bayeva, Marina; Khechaduri, Arineh; Wu, Rongxue et al. (2013) ATP-binding cassette B10 regulates early steps of heme synthesis. Circ Res 113:279-87
Bayeva, Marina; Sawicki, Konrad Teodor; Ardehali, Hossein (2013) Taking diabetes to heart--deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. J Am Heart Assoc 2:e000433
Jankowska, Ewa A; Malyszko, Jolanta; Ardehali, Hossein et al. (2013) Iron status in patients with chronic heart failure. Eur Heart J 34:827-34
Bayeva, Marina; Gheorghiade, Mihai; Ardehali, Hossein (2013) Mitochondria as a therapeutic target in heart failure. J Am Coll Cardiol 61:599-610

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