One of the most common complications of prematurity is developmental arrest of pulmonary tissue, named bronchopulmonary dysplasia (BPD). The BPD is tightly associated with increased incidence of neurological handicap, asthma and cardiac failure. All current therapeutic strategies are based on a long-time clinical observation that BPD affects developing lungs only if pulmonary tissue is subjected to stress (mechanical ventilation, hyperoxic exposure, fluid overload, infection etc). However, the lack of understanding the mechanisms responsible for the link between these stresses and BPD substantially limits any further efforts to combat this disease. This proposal is focused on testing a novel hypothesis that one of the primary mechanisms of alveolar developmental arrest in BPD is mitochondrial failure to provide an adequate energy for normal tissue growth. Our preliminary data demonstrates that during hyperoxic stress lung mitochondria rapidly decrease their ability to produce energy secondary to a failure of cellular respiration. Hyperoxic mice exhibited a profound inhibition of mitochondrial complex-I (C-I) activity, the event tightly coupled with the extent of pulmonary developmental failure. This suggests that mitochondrial dysfunction may represent a primary mechanism for arrested alveolarization. There are three aims: (1) To determine if excessive generation of ROS in pulmonary mitochondria in response to hyperoxic stress results in inhibition of C-I. (2) To determine whether the inhibition of C-I (1) independently from ATP-production or (2) secondary to decrease of ATP production downregulates the expression and synthesis of vascular endothelial growth factor (VEGF), a protein vital for normal alveolar development. (3) To determine if nutritional supplementation with mitochondrial Complex-II dependent substrates restores ATP production rate and attenuates cell growth failure induced by hyperoxic stress. Importantly, studies designed for these aims will also serve as a major research-training vehicle for PI.
All aims will be completed within four years eventuating in submission of RO1 proposal. Thus, this proposal is an initial large-scale research project for this mentored research award which will (a) elucidate the mechanism for mitochondrial dysfunction, highlight molecular targets for potential therapeutic strategies in BPD and (b) serve as a critical milestone for PI in his path to independence. .
Alveolar developmental arrest, namely bronchopulmonary dysplasia remains the main cause of morbidity and mortality in premature infants. This proposal is focused on novel observation made by the primary investigator: the alveolar developmental arrest is strongly associated with severe mitochondrial dysfunction. By the end of tenure of this grant the mechanisms responsible for pulmonary mitochondrial inhibition induced by exogenous stress (hyperoxia) will be determined. Potentially, this will highlight a novel therapeutic strategy to combat bronchopulmonary dysplasia.
|Ratner, Veniamin; Sosunov, Sergey A; Niatsetskaya, Zoya V et al. (2013) Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice. Am J Respir Cell Mol Biol 49:943-50|
|Niatsetskaya, Zoya V; Charlagorla, Pradeep; Matsukevich, Dzmitry A et al. (2012) Mild hypoxemia during initial reperfusion alleviates the severity of secondary energy failure and protects brain in neonatal mice with hypoxic-ischemic injury. J Cereb Blood Flow Metab 32:232-41|
|Ten, Vadim S; Yao, Jun; Ratner, Veniamin et al. (2010) Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury. J Neurosci 30:2077-87|
|Ratner, Veniamin; Starkov, Anatoly; Matsiukevich, Dzmitry et al. (2009) Mitochondrial dysfunction contributes to alveolar developmental arrest in hyperoxia-exposed mice. Am J Respir Cell Mol Biol 40:511-8|
|Ratner, Veniamin; Slinko, Siarhei; Utkina-Sosunova, Irina et al. (2009) Hypoxic stress exacerbates hyperoxia-induced lung injury in a neonatal mouse model of bronchopulmonary dysplasia. Neonatology 95:299-305|