The candidate, Hossein Ardehali, M.D., Ph.D., is completing his training in Cardiovascular Medicine at the Johns Hopkins University Medical Center. As of July 1, 2004, he will be an Assistant Professor of Medicine in the Division of Cardiology at Johns Hopkins. The candidate has a solid interest in pursuing basic science research along with patient care in an academic institution. Johns Hopkins provides an excellent academic environment for young faculty to ensure their success in their scientific endeavors. Dr. Ardehali's mentor, Dr. Eduardo Marban, is a world-renown leader in cardiovascular biology, and his laboratory has an excellent track record of producing independent clinician scientists in cardiovascular biology. Dr. Ardehali's long-term goals are to become an independent 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 mentored research, didactic course work and professional scientific skills to launch a successful career as an independent investigator. Evidence suggests that brief ischemic episodes may invoke a process that can protect against future ischemic insults, a mechanism known as ischemic preconditioning (IPC). The mitochondrial ATP-sensitive K+ channel (mitoKATP) has been shown to be a key player in the process of IPC and is an inhibitor of apoptosis. However, the molecular structure of mitoKATP remains unknown. In preliminary data presented in this grant, the applicant has shown that a macromolecular protein complex in the mitochondrial inner membrane confers mitoKATP channel activity. The function of one member of this complex, mitochondrial ATP-Binding Cassett Protein-1 (mABC1) is not known, however, its yeast analog is thought to play a key role in protection against oxidant stress. The long-term objective of this proposal is to study whether mABC1 protein plays a role in protection of cells against ischemia and oxidant stress.
In Aim 1, the applicant will evaluate the effect of mABC1 overexpression on cellular protection.
In Aim 2, SiRNA technology will be used to downregulate mABC1 expression and study whether this would result in an exaggerated ischemic or oxidant damage to the cells.
Aim 3 will focus on identifying substrate(s) that are transported by mABC1. The central thesis of this proposal is that mABC1 protein plays a key role in cellular protection against oxidant stress and ischemia. The experiments proposed herein are logical continuation of our attempt to understand the process of ischemic preconditioning and cellular protection against ischemia. The proposed development plan is designed to provide the mentorship, resources and supportive environment to build a successful career as an independent clinician scientist.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL079387-03
Application #
7226289
Study Section
Special Emphasis Panel (ZHL1-CSR-M (O1))
Program Officer
Commarato, Michael
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$125,743
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Bayeva, Marina; Khechaduri, Arineh; Wu, Rongxue et al. (2013) ATP-binding cassette B10 regulates early steps of heme synthesis. Circ Res 113:279-87
Wu, Rongxue; Smeele, Kirsten M; Wyatt, Eugene et al. (2011) Reduction in hexokinase II levels results in decreased cardiac function and altered remodeling after ischemia/reperfusion injury. Circ Res 108:60-9
Mutharasan, R Kannan; Nagpal, Varun; Ichikawa, Yoshihiko et al. (2011) microRNA-210 is upregulated in hypoxic cardiomyocytes through Akt- and p53-dependent pathways and exerts cytoprotective effects. Am J Physiol Heart Circ Physiol 301:H1519-30
Forini, Francesca; Lionetti, Vincenzo; Ardehali, Hossein et al. (2011) Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats. J Cell Mol Med 15:514-24
Decker, Robert S; Rines, Amy K; Nakamura, Sakie et al. (2010) Phosphorylation of contractile proteins in response to alpha- and beta-adrenergic stimulation in neonatal cardiomyocytes. Transl Res 155:27-34
Wyatt, Eugene; Wu, Rongxue; Rabeh, Wael et al. (2010) Regulation and cytoprotective role of hexokinase III. PLoS One 5:e13823
Gordon, Leo I; Burke, Michael A; Singh, Amareshwar T K et al. (2009) Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J Biol Chem 284:2080-7
Burke, Michael A; Mutharasan, R Kannan; Ardehali, Hossein (2008) The sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel. Circ Res 102:164-76
Sun, Lin; Shukair, Shetha; Naik, Tejaswitha Jairaj et al. (2008) Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and II. Mol Cell Biol 28:1007-17
Burke, Michael A; Ardehali, Hossein (2007) Mitochondrial ATP-binding cassette proteins. Transl Res 150:73-80

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