The peripheral arterial chemoreceptors in the carotid body are critical in regulating ventilation in response to changes in oxygen tension, and they provide essential sensory input during early development to stabilize and maintain breathing throughout life. Exposure to chronic hypoxia and hyperoxia (oxygen stress) during early postnatal development significantly depresses ventilatory responses to acute hypoxia in both newborn animals and human infants born prematurely. This ventilatory depression can be life-long in animals exposed to chronic hyperoxia and only partially reversible in animals exposed to chronic hypoxia during early postnatal development. Premature infants are particularly vulnerable to the effects of hyperoxia since antioxidant defenses are reduced. Furthermore, these infants are at high risk for persistent apnea and bradycardia, reduced arousal responses during sleep, and sudden death which are all adverse physiological events related to perturbations in chemoreceptor function. Adenosine modulates chemoreceptor activity and has been shown in other model systems to be critically important in mediating cytoprotection from oxidative stress. This proposal will test the overall hypothesis that oxygen stress (hypoxia and hyperoxia) during early postnatal development depends on the presence of functional adenosine A1 and A2a receptors on type 1 cells and sensory neurons in the carotid body, and the long term response of oxygen stress perturbs the balance of excitatory and inhibitory adenosine mechanisms resulting in decreased excitability of first order sensory neurons thereby blunting chemoreceptor responses. We will interrogate this hypothesis with 3 specific aims that will determine the effect of development on 1) the functional neuoranatomy of the adenosine system in the carotid body, 2) the correlation between hypoxic induced adenosine and ATP release (measured with novel biosensors) with single-unit sensory nerve activity, 3) the perturbations induced by chronic hypoxic and hyperoxic exposure (in vivo) on both the ultrastructure of carotid body and alterations in the adenosine neuromodulator system, 4) the role of reactive oxygen species, nuclear factor - kB, and adenosine receptors in mediating hyperoxic induced cytotoxicity (ex vivo) in the carotid body and sensory neurons. ? ?
| Chavez-Valdez, Raul; Mason, Ariel; Nunes, Ana R et al. (2012) Effect of hyperoxic exposure during early development on neurotrophin expression in the carotid body and nucleus tractus solitarii. J Appl Physiol 112:1762-72 |
| Hecht, Elena; Usmani, Shariq M; Albrecht, Susanne et al. (2011) Atomic force microscopy of microvillous cell surface dynamics at fixed and living alveolar type II cells. Anal Bioanal Chem 399:2369-78 |
| Chavez-Valdez, Raul; Wills-Karp, Marsha; Ahlawat, Rajni et al. (2009) Caffeine modulates TNF-alpha production by cord blood monocytes: the role of adenosine receptors. Pediatr Res 65:203-8 |
| Weber, Cornelia; Gauda, Estelle; Mizaikoff, Boris et al. (2009) Developmental aspects of amperometric ATP biosensors based on entrapped enzymes. Anal Bioanal Chem 395:1729-35 |
| Masson, Jean-Francois; Kranz, Christine; Mizaikoff, Boris et al. (2008) Amperometric ATP microbiosensors for the analysis of chemosensitivity at rat carotid bodies. Anal Chem 80:3991-8 |
| Masson, Jean-Francois; Gauda, Estelle; Mizaikoff, Boris et al. (2008) The interference of HEPES buffer during amperometric detection of ATP in clinical applications. Anal Bioanal Chem 390:2067-71 |
| Masson, Jean-Francois; Kranz, Christine; Mizaikoff, Boris (2007) Modeling the response function of dual-enzyme microbiosensors. Anal Chem 79:8531-8 |
| Gauda, Estelle B; Cristofalo, Elizabeth; Nunez, Jeanne (2007) Peripheral arterial chemoreceptors and sudden infant death syndrome. Respir Physiol Neurobiol 157:162-70 |
