Radiation induced cell death, inflammation cell death and multiple organ dysfunction necessitates employment of multiple sequential therapeutic interventions for effective radiomitigation. Our previously established oxidation of a mitochondria-specific phospholipid, cardiolipin (CL), as a required step in apoptosis resulted in the design of three new classes of mitochondria-targeted early stage radiomitigators. Recently, we discovered a new mitochondrial regulatory pathway for the CL-dependent production of lipid mediators activated in vivo during acute radiation injury. In this project, our central hypothesis is: Radiation induced systemic responses involve a series of Ca2+-independent consecutive reactions of CL oxidation and hydrolysis leading to the formation of regulatory lipid mediators with critical roles in radiation injury. These reactions include enzymatic oxidation of polyunsaturated CL species. The latter undergo hydrolysis by Ca -independent phospholipases A2 (PLA2) - 2+ iPLA2-? or LpPLA2 - to produce diversified FFAox as well as oxygenated and non-oxygenated lyso-CLs ? lipid mediators of systemic response.
Three Specific Aims have been developed:
In Specific Aim 1 we will use oxidative lipidomics to identify and quantitatively characterize molecular diversification of CL oxidation products and CLox-derived lipid mediators ? FFAox and lyso-CL ? in tissues and plasma at critical stages of radiation injury - apoptotic/necrotic cell death, breakage of GI epithelial barrier and penetration of bacterial pathogens into circulation and inflammatory response - culminating in multiple organ dysfunction in w/t and transgenic mice (iPLA2-? k/o, LpPLA2 k/o, Gpx4 conditional k/o) exposed to three doses of TBI.
Specific Aim 2 will determine the effectiveness of small molecule inhibitors of enzymatic CLox hydrolysis by iPLA2-? and LpPLA2 in: i) suppressing the production of lipid mediators, ii) affecting critical stages of systemic response to irradiation, iii) mitigating radiation injury.
Specific Aim 3 will establish the molecular mechanisms through which a specific lipid mediator of neutrophils with anti-bacterial activity, Hepoxilin A3 (HXA3), ? affects radiation damage of GI epithelium and determine the optimal timing for control of HXA3 production using small molecule regulators with maximal radiomitigative effect. These highly innovative approaches combining analytical power of oxidative lipidomics with characterization of diversified systemic responses as well as genetic manipulations and pharmacological interventions will lead to the discovery of new classes of delayed radiomiomitigators.
| Lou, Wenjia; Ting, Hsiu-Chi; Reynolds, Christian A et al. (2018) Genetic re-engineering of polyunsaturated phospholipid profile of Saccharomyces cerevisiae identifies a novel role for Cld1 in mitigating the effects of cardiolipin peroxidation. Biochim Biophys Acta Mol Cell Biol Lipids 1863:1354-1368 |
| Anthonymuthu, Tamil S; Kenny, Elizabeth M; Lamade, Andrew M et al. (2018) Oxidized phospholipid signaling in traumatic brain injury. Free Radic Biol Med 124:493-503 |
| Hassannia, Behrouz; Wiernicki, Bartosz; Ingold, Irina et al. (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest 128:3341-3355 |
| Conrad, Marcus; Kagan, Valerian E; Bayir, Hülya et al. (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32:602-619 |
| Stoyanovsky, Anastas D; Stoyanovsky, Detcho A (2018) 1-Oxo-2,2,6,6-tetramethylpiperidinium bromide converts ?-H N,N-dialkylhydroxylamines to nitrones via a two-electron oxidation mechanism. Sci Rep 8:15323 |
| Zhou, Shuanhu; Glowacki, Julie (2018) Dehydroepiandrosterone and Bone. Vitam Horm 108:251-271 |
| Robinson, Andria R; Yousefzadeh, Matthew J; Rozgaja, Tania A et al. (2018) Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol 17:259-273 |
| Gaschler, Michael M; Andia, Alexander A; Liu, Hengrui et al. (2018) FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 14:507-515 |
| Tyurina, Yulia Y; Shrivastava, Indira; Tyurin, Vladimir A et al. (2018) ""Only a Life Lived for Others Is Worth Living"": Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions. Antioxid Redox Signal 29:1333-1358 |
| Schlattner, Uwe; Tokarska-Schlattner, Malgorzata; Epand, Richard M et al. (2018) NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy. Lab Invest 98:228-232 |
Showing the most recent 10 out of 203 publications
