Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are among the most devastating causes of fatality in critically ill patients. Recently, accumulating evidence shows that mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an invaluable shield against oxidative stress mediated damage. During the last cycle of our grant, while studying the mechanisms by which suppressor of cytokine signaling 1 (SOCS-1) protects against ALI, we discovered that ALDH2 activity is restored in SOCS-1 overexpressed mice. Now, our efforts focus on mitochondria and mitochondrial redox regulation in ALI/ARDS. Our previous studies indicate that reactive oxygen species (ROS), produced by hyperoxia, are key factors in causing mitochondrial damage. Based on numerous studies of ROS involvement in ALI, many trials have targeted ROS for the treatment of ALI and ARDS. Unfortunately, molecular instability makes ROS challenging therapeutic targets, and treatment with anti- oxidants (which target ROS) does not rectify mitochondrial damage. However, more plausible targets may be the stable secondary ROS intermediates, such as 4-hydroxy-2-nonenal (4-HNE). 4-HNE, a toxic lipid peroxidation product that disrupts mitochondrial bioenergetics, plays a causal role in oxidative stress diseases. Therefore, clearing 4-HNE and preserving vital mitochondrial homeostasis is a logical approach for the development of new therapies. Studies in models of various oxidative stress-mediated injuries, have shown that ALDH2 is a powerful endogenous enzyme that effectively protects against oxidative stress through the clearance of 4-HNE. Despite our expanding knowledge regarding the function of ALDH2 in other diseases, there is a lack in our understanding of ALDH2 involvement in ALI and ARDS. We hypothesize that activation of ALDH2 protects against hyperoxia-induced ALI (HALI) via restoration of A-kinase anchor protein 121 (AKAP121) levels, which preserves mitochondrial function. We propose the following specific aims to investigate our hypothesis:
Aim 1 : Elucidate the mechanism of ALDH2 inactivation, Siah2 accumulation, and AKAP121 degradation.
Aim 2 : Elucidate the mechanism by which AKAP121 loss potentiates ALDH2 deficiency-induced HALI.
Aim 3 : Determine the therapeutic role of ALDH2 activation in hyperoxic and infectious ALI models. Our proposed studies will unveil a new molecular target (ALDH2) in ALI/ARDS pathogenesis, reveal its biological significance in regulating AKAP121 levels, and decipher its connection to mitochondrial dysfunction.
The goal of the proposed research is to develop a therapy that will improve survival and standard of living to individuals affected by hyperoxia-induced lung injury using animal models. It is important to develop this therapy since current treatment is ineffective in resolving the insult and is limited to supportive care.
| Saco, Tara V; Breitzig, Mason T; Lockey, Richard F et al. (2018) Epigenetics of Mucus Hypersecretion in Chronic Respiratory Diseases. Am J Respir Cell Mol Biol 58:299-309 |
| Narala, Venkata Ramireddy; Fukumoto, Jutaro; Hernández-Cuervo, Helena et al. (2018) Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice. Am J Physiol Lung Cell Mol Physiol 314:L860-L870 |
| Sriperumbudur, Amruthansh; Breitzig, Mason; Lockey, Richard et al. (2017) Hedgehog: the key to maintaining adult lung repair and regeneration. J Cell Commun Signal 11:95-96 |
| Tian, Zhi; Zhang, Hui; Dixon, Jendayi et al. (2017) Cigarette Smoke Impairs A2A Adenosine Receptor Mediated Wound Repair through Up-regulation of Duox-1 Expression. Sci Rep 7:44405 |
| Galam, Lakshmi; Soundararajan, Ramani; Breitzig, Mason et al. (2016) SOCS-1 rescues IL-1?-mediated suppression of epithelial sodium channel in mouse lung epithelial cells via ASK-1. Oncotarget 7:29081-91 |
| Soundararajan, Ramani; Stearns, Timothy M; Czachor, Alexander et al. (2016) Global gene profiling of aging lungs in Atp8b1 mutant mice. Aging (Albany NY) 8:2232-2252 |
| Fukumoto, Jutaro; Cox Jr, Ruan; Fukumoto, Itsuko et al. (2016) Deletion of ASK1 Protects against Hyperoxia-Induced Acute Lung Injury. PLoS One 11:e0147652 |
| Fukumoto, Jutaro; Soundararajan, Ramani; Leung, Joseph et al. (2016) The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis. Aging (Albany NY) 8:3091-3109 |
| Galam, Lakshmi; Rajan, Ashna; Failla, Athena et al. (2016) Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression. Am J Physiol Lung Cell Mol Physiol 310:L572-81 |
| Patel, Priyanshi; Lockey, Richard F; Kolliputi, Narasaiah (2015) Can inflammation regulate systemic aging? Exp Gerontol 67:1-2 |
Showing the most recent 10 out of 48 publications
