Mechanisms of sleep and sleep apnea

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Summary – Overall Section The overall goal of this Program Project is to identify and manipulate brain circuitry that mediates the respiratory and arousal responses to hypercarbia and hypoxia, so that we may improve therapy for a variety of hypoventilation syndromes including obstructive sleep apnea (OSA), opioid-induced respiratory depression (OIRD), and obesity-hypoventilation syndrome (OHS). In the current PPG we used single cell RNA sequencing (scRNA-Seq) to identify genetically specified cell subtypes in the parabrachial (PB)/Kölliker-Fuse (KF) complex and the medullary raphe that are key components of this circuitry. We now seek to leverage this information by using cutting-edge molecular tools to identify the functions of these cell types, their targets, and the receptor mechanisms involved, and to define targets for rational pharmacological therapy of hypoventilation syndromes. Project 1 will identify the cell types in the PB/KF that respond to hypoxia and hypercarbia, characterize their physiological roles and how they are affected by morphine, and identify synaptic mechanisms by which they activate their targets in mouse models of OSA and OIRD. Project 2 will examine the role of orexin inputs to brainstem neurons in the PB/KF and medullary raphe that drive ventilation in OHS and OIRD, their ability to augment respiratory function, and whether orexin agonists can improve breathing in these mouse models. Project 3 will identify other forebrain sites that activate PB/KF respiratory neurons during EEG arousal and the synaptic mechanisms that they use to augment respiration in OSA and OIRD models. Project 4 will examine medullary raphe cell subtypes that augment respiratory motor responses during models of OSA and OIRD, and whether orexin or TRH agonists can increase their responses and ventilation in those models. Project 5 will test hypotheses from Projects 1-4 for new therapies for OSA and OIRD in human subjects. In specific, it will test the effects of the orexin agonist danavorextan and the TRH agonist taltirelin, in controls and OSA subjects at baseline and after morphine. These Projects will interact extensively with each other, and with the Molecular Biology Core B and the Cellular Neurophysiology Core C, under the aegis of Administrative Core A, to accelerate the advance of therapies for OSA, OIRD, and OHS from the bench to the bedside.