The central hypothesis of this competitive renewal is formulated on the basis of two key developments in the field of ischemia biology and cardioprotection: (i) the identification of multiprotein complex formation as a means for cardioprotective signaling and (ii) the establishment of the mitochondria as a critical organelle for cell death and survival. The functional link between these two developments is mitochondrial permeability transition (MPT) in ischemic injury. MPT involves impaired mitochondrial function leading to cell death and is carried out by a multiprotein complex, the MPT pore. Deciphering the proteomic basis of the MPT pore and elucidating its role in cardioprotection constitute the major goals of this application. The proposed studies will focus on nitric oxide (NO)-induced late preconditioning (PC), a well-characterized pharmacological means of cardioprotection with a poorly-defined proteomic basis for its underlying cellular mechanisms. To achieve our goals, the application directs its effort at two targets: the Oracle isozymes, a novel family of scaffolding proteins critical to NO protective signaling, and the subproteome of ANT1, a repertoire of ANT1-associating proteins that are essential to MPT pore function. We hypothesize that attenuated propensity for mitochondrial permeability transition is an essential signaling event in NO-mediated cardioprotection and that the Oracle family of proteins plays a critical role in this process by modulating the ANT1 subproteome and contributing to the protection of mitochondrial function.
Three specific aims, with tightly related experimental protocols are proposed.
Aim 1 will establish the essential role of Oracle, a molecular backbone of signaling complexes, in NO-induced preconditioning.
Aim 2 will build upon knowledge gained in Aim 1 to elucidate the function of the MPT pore in NO-mediated cardioprotection and determine the role of Oracle in this process. Finally, Aim 3 will define a subproteome, composed of ANT1-associating proteins, which is critical to the regulation of MPT pore function in cardiac mitochondria. Importantly, for the first time, the proteomic basis of the participation of the MPT pore in NO protection will be determined and the role of Oracle in the assembly of this subproteome will be fully characterized. A comprehensive strategy encompassing pharmacological methods, transgenic models, and proteomic characterization is proposed. These studies will elucidate the proteomic basis of NO preconditioning, define mechanisms underlying ANT1 regulation, and identify novel molecular targets that are critical to the modulation of MPT pore function. Thus, the findings will have broad implications for future investigations concerning pharmacological cardioprotective interventions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-C (02))
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Liang, Isabella Y
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Gomes, Aldrin V; Young, Glen W; Wang, Yueju et al. (2009) Contrasting proteome biology and functional heterogeneity of the 20 S proteasome complexes in mammalian tissues. Mol Cell Proteomics 8:302-15
Mayr, Manuel; Liem, David; Zhang, Jun et al. (2009) Proteomic and metabolomic analysis of cardioprotection: Interplay between protein kinase C epsilon and delta in regulating glucose metabolism of murine hearts. J Mol Cell Cardiol 46:268-77
Zong, Chenggong; Young, Glen W; Wang, Yueju et al. (2008) Two-dimensional electrophoresis-based characterization of post-translational modifications of mammalian 20S proteasome complexes. Proteomics 8:5025-37
Liem, David A; Zhao, Peng; Angelis, Ekaterini et al. (2008) Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/reperfusion injury. J Mol Cell Cardiol 45:610-6
Zhang, Jun; Liem, David A; Mueller, Michael et al. (2008) Altered proteome biology of cardiac mitochondria under stress conditions. J Proteome Res 7:2204-14
Lu, Haojie; Zong, Chenggong; Wang, Yueju et al. (2008) Revealing the dynamics of the 20 S proteasome phosphoproteome: a combined CID and electron transfer dissociation approach. Mol Cell Proteomics 7:2073-89
Zhang, Jun; Li, Xiaohai; Mueller, Michael et al. (2008) Systematic characterization of the murine mitochondrial proteome using functionally validated cardiac mitochondria. Proteomics 8:1564-75
Liem, David A; Honda, Henry M; Zhang, Jun et al. (2007) Past and present course of cardioprotection against ischemia-reperfusion injury. J Appl Physiol 103:2129-36
Drake, Thomas A; Ping, Peipei (2007) Thematic review series: systems biology approaches to metabolic and cardiovascular disorders. Proteomics approaches to the systems biology of cardiovascular diseases. J Lipid Res 48:1-8
Zong, Chenggong; Gomes, Aldrin V; Drews, Oliver et al. (2006) Regulation of murine cardiac 20S proteasomes: role of associating partners. Circ Res 99:372-80

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