Wednesday, February 5, 2025
2/5/2025
Proposal Summary Breathing is a vital process that maintains oxygen and carbon dioxide homeostasis, and its dysregulation leads to various and often devastating conditions. Effective pharmaceutical treatments for patients in respiratory abnormalities are severely limited due to our lack of knowledge on the neurological mechanisms controlling breathing and how they may go awry under pathological conditions. Sighs are long, deep breaths with a bimodal inspiration that occur spontaneously every several minutes to reverse the alveolar collapse (atelectasis) and maintain normal lung function. Sighing has also been implicated in various pathological conditions, including sudden infant death syndrome. The long-term goal of my laboratory is to understand the neural control of breathing patterns, including sighing, and how it fails in pathological conditions. In this project, we propose to understand how the central control mechanism of sighing is regulated by physiological sigh- inducing stimuli, including hypoxia and sleep-wake states. We recently identified that the mouse brainstem neurons expressing neuromedin B (Nmb) or gastrin releasing peptide (Grp) comprise the core components of a dedicated sigh control circuit. Leveraging this endogenous pathway and circuit underlying sighing, we will integrate mouse genetics, optogenetics and chemogenetics, genetic ablation, neural circuit tracing, functional imaging, and physiological assays, to genetically and functionally dissect the neural control circuits in mouse in vivo experiments. In Aim 1, we will use optogenetics, genetic ablation, and circuit tracing to define the neural circuit underlies hypoxia-induced sighing. In Aim 2, we will examine the role of input neurons to the sigh circuit in regulating sighing as a function of sleep-wake state. In Aim 3, we will monitor the calcium activity of the sigh control neurons during basal and induced sighs in order to understand the neuronal basis underlying the generation of sighing and other breathing patterns in physiological conditions. The expected outcomes are to lead to a better understanding of the function of the sigh control circuits, and provide an improved foundation for understanding how different breathing patterns are controlled and how physiological states in turn dictate switches in the breathing patterns. These outcomes will have an important impact by revealing the mechanistic basis for the pathophysiology of breathing disorders and identifying targeted pharmacological approaches for new treatment modalities in a variety of clinical scenarios.
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