[R01] Effects of perinatal ethanol exposure on immature respiratory control
Ente: National Institute on Alcohol Abuse and Alcoholism
Scadenza: 2031-03-31
Importo max: 550.442 EUR
Paese: US
Descrizione
Apnea of prematurity (AOP) is a common ailment of early preterm infants (<32 weeks gestation, >60,000 born
each year in the USA). It is characterized by episodic cessation of breathing and often accompanied by
intermittent hypoxemia (IH). IH is associated with poor neurodevelopmental outcomes. In animal models, a single
day exposure to ethanol in a neonatal rat during a stage of development equivalent to that of a preterm infant
reduced the volume of the brainstem resulting in major disturbances in control of respiration. Preterm infants
(whose brainstems are at the same stage of development as third trimester fetuses) are exposed to ethanol used
as an excipient for medications administered in the neonatal intensive care unit. The neurons of the nucleus
tractus solitarius (nTS) are an essential part of the neural circuitry having a critical role in governing respiratory
drive and apnea. In the preterm newborn, the nTS of the brain is immature and undergoing rapid development:
Neurons are differentiating and extending neurites, forming synapses and undergoing myelination. These
processes depend on dynamic microdomains of the plasma membrane called lipid rafts. Lipid rafts regulate
activity of ion channels, signal transduction and protein trafficking. We hypothesize that ethanol disrupts control
of respiration, ion channel function, and lipid rafts leading to perturbations in the nTS, and that choline, a known
neuroprotectant, reduces the impact of ethanol on both respiratory drive, ion channel function and lipid rafts. We
have previously shown that 1) ethanol disrupts the function of a lipid raft associated protein both in vitro and ex
vivo, and alters cerebellar mediated behaviors, and that 2) choline confers resistance to the effects of ethanol
on both the lipid raft associated protein and behaviors. These results have put us in a position to accomplish the
following novel and clinically relevant goals: 1) explore the effects of ethanol on lipid rafts in the nTS and their
response to choline; 2) determine the impact of ethanol with or without choline on nTS neurotransmission and
excitability; 3) correlate these neurochemical, anatomical and neurophysiological effects of ethanol with
measures of respiratory drive and apnea and how they are protected by choline administration; and 4) determine
the distribution of urine concentrations of ethyl glucuronide and ethyl sulfate (EtOH biomarkers) and their
association with ethanol-containing drug exposure, in a cohort of preterm infants previously enrolled in the
PreVent Study. We predict that lipid raft dysfunction even by brief ethanol exposure will precede changes in
neuronal excitability and respiratory drive, and all changes in outcomes will be lessened by choline. We also
predict that preterm infants will have high levels of ethanol metabolites measurable at 1 week and one month of
age and that urine EtOH biomarker levels will be associated with gestational, postnatal and corrected age, and
exposur
Istituzione: CASE WESTERN RESERVE UNIVERSITY
PI: CYNTHIA FRANCES BEARER, Peter MacFarlane
Progetto: 1R01AA032476-01A1
Settori: National Institute on Alcohol Abuse and Alcoholism
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.