The overall goal of our research program is to elucidate endogenous and other mechanisms of protection against ischemia-reperfusion (IR) injury, and to exploit this knowledge to develop new therapies for IR disease conditions such as heart attack and stroke. Many cardioprotective strategies appear to converge on mitochondrial potassium channels as necessary and sufficient effectors of protective signaling. However, the identity and regulation of these channels remains controversial. Our published research to date, and exciting preliminary data contained herein, have directed our focus to a novel mitochondrial K+ channel that is required for protection and has not previously been implicated in protective signaling. Notably, absence of this channel appears to yield a metabolic phenotype. We have also identified a novel class of endogenous channel modulators. In this proposal, Aim 1 will characterize the channel and its role in cardioprotection, Aim 2 will investigate links between the channel and cardiac metabolism, and Aim 3 will study its regulation by endogenous signals. We will use a variety of state-of-the -art techniques, including patch-clamp of mitoplasts (isolated mitochondrial inner membranes), and Seahorse XF methodology to assess cardiomyocyte bioenergetics. This dual-PI proposal draws on the expertise of both investigators (Brookes - mitochondrial biology, metabolic screening, cardiac patho-physiology;Nehrke - ion channels, mouse genetics, mitochondrial physiology). Our productive track-record (8 original research articles and 3 reviews funded by this project in 3 years) imparts a high probability that the completion of these 3 aims will yield critical information about this channel, which is a novel potential drug target for cardioprotection.

Public Health Relevance

Heart attack is responsible for >220,000 deaths per year in the USA, and a further ~380,000 patients undergo cardiac surgery every year. Hence there is a drastic need for therapies to avoid myocardial injury. We have identified a novel molecular target (a potassium channel in mitochondria) whose activity is both necessary and sufficient for protection from ischemia. The proposed project will investigate the properties of this channel and its role in cardio protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM087483-05
Application #
8652105
Study Section
Special Emphasis Panel (ZRG1-CVRS-M (02))
Program Officer
Nie, Zhongzhen
Project Start
2010-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$259,998
Indirect Cost
$89,998
Name
University of Rochester
Department
Anesthesiology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Queliconi, Bruno B; Kowaltowski, Alicia J; Nehrke, Keith (2014) An anoxia-starvation model for ischemia/reperfusion in C. elegans. J Vis Exp :
Wojtovich, Andrew P; Foster, Thomas H (2014) Optogenetic control of ROS production. Redox Biol 2:368-76
Raphemot, Rene; Swale, Daniel R; Dadi, Prasanna K et al. (2014) Direct activation of ?-cell KATP channels with a novel xanthine derivative. Mol Pharmacol 85:858-65
Wojtovich, Andrew P; Urciuoli, William R; Chatterjee, Shampa et al. (2013) Kir6.2 is not the mitochondrial KATP channel but is required for cardioprotection by ischemic preconditioning. Am J Physiol Heart Circ Physiol 304:H1439-45
Queliconi, Bruno B; Marazzi, Thire B M; Vaz, Sandra M et al. (2013) Bicarbonate modulates oxidative and functional damage in ischemia-reperfusion. Free Radic Biol Med 55:46-53
Wojtovich, Andrew P; Smith, C Owen; Haynes, Cole M et al. (2013) Physiological consequences of complex II inhibition for aging, disease, and the mKATP channel. Biochim Biophys Acta 1827:598-611
Wojtovich, Andrew P; DiStefano, Peter; Sherman, Teresa et al. (2012) Mitochondrial ATP-sensitive potassium channel activity and hypoxic preconditioning are independent of an inwardly rectifying potassium channel subunit in Caenorhabditis elegans. FEBS Lett 586:428-34
Wojtovich, Andrew P; Nadtochiy, Sergiy M; Brookes, Paul S et al. (2012) Ischemic preconditioning: the role of mitochondria and aging. Exp Gerontol 47:1-7
Wojtovich, Andrew P; Sherman, Teresa A; Nadtochiy, Sergiy M et al. (2011) SLO-2 is cytoprotective and contributes to mitochondrial potassium transport. PLoS One 6:e28287
Queliconi, Bruno B; Wojtovich, Andrew P; Nadtochiy, Sergiy M et al. (2011) Redox regulation of the mitochondrial K(ATP) channel in cardioprotection. Biochim Biophys Acta 1813:1309-15

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