Area:
Neuroscience Biology, Physiology Biology
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High-probability grants
According to our matching algorithm, Tracy L. Baker-Herman is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2011 — 2015 |
Baker-Herman, Tracy Lee |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Inactivity-Induced Respiratory Plasticity @ University of Wisconsin-Madison
DESCRIPTION (provided by applicant): The fundamental hypothesis guiding this proposal is that reduced synaptic inputs to respiratory motor neurons elicits compensatory plasticity, preserving respiratory motor output in a range compatible with life. Our specific goal in the present project period is to investigate cellular mechanisms giving rise to inactivity-induced phrenic motor facilitation (iPMF), a persistent increase in phrenic burst amplitude following prolonged decreases in phrenic neural activity. Two distinct methods of reducing phrenic activity will be studied in anesthetized rats: one that reduces overall activity in the respiratory network (hypocapnia) and another that specifically decreases spinal synaptic inputs to phrenic motor neurons (C2 axon conduction block). The iPMF evoked by these methods exhibits striking similarities, yet may have important differences. Hypocapnia and C2 conduction block both elicit iPMF (i.e., increased amplitude), but only hypocapnia elicits phrenic burst frequency facilitation suggesting the possibility of that iPMF arises from multiple mechanisms depending on whether neural activity was reduced locally versus globally. In this project, we will focus on spinal mechanisms leading to iPMF. Our working model is that reduced synaptic input to phrenic motor neurons stimulates TNF1 release in the phrenic motor nucleus (Aim 1), activating atypical PKC (aPKC) isoforms in or near phrenic motor neurons that give rise to iPMF (Aims 2 and 3). We further propose that iPMF is subject to regulatory constraints, similar to other forms of neuroplasticity. By investigations of a unique sub-strain of Sprague Dawley rats, we will gain critical insights concerning mechanisms that constrain iPMF. In specific, we hypothesize that greater constitutive NMDA-glutamateric receptor activity constrains iPMF in this rat sub-strain (Aim 4), possibly due to genetic or epigenetic factors. Since failure to elicit iPMF may contribute to ventilatory control disorders of importance to human health, such as ventilatory weaning failure following prolonged ventilatory support, differences in constitutive NMDA receptor activity may differentiate patients that successfully wean from ventilatory support versus those that do not. A detailed understanding of cellular cascades giving rise to iPMF is essential to understand the physiological role of this highly novel form of plasticity, and-importantly-to identify promising therapeutic targets for pharmacological interventions to treat respiratory control disorders. PUBLIC HEALTH RELEVANCE: Since breathing is necessary for life, failure to restore adequate breathing after prolonged periods of ventilatory support represents a serious clinical problem. In this project we will investigate a highly novel mechanism of spinal cord plasticity induced by periods of reduced breathing effort. Through a detailed understanding of this mechanism, we hope to understand the neural basis of ventilator weaning failure and to develop treatments for patients that have difficulty resuming unassisted breathing.
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1 |
2017 |
Baker-Herman, Tracy Lee |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms and Significance of Inactivity-Induced Respiratory Plasticity @ University of Wisconsin-Madison
PROJECT SUMMARY/ABSTRACT In the first funding period, we discovered that local mechanisms sense and respond to a reduction in synaptic inputs to phrenic motor neurons to elicit compensatory enhancement of phrenic motor output, a novel form of plasticity that we termed inactivity-induced phrenic motor facilitation (iPMF). We defined key cellular pathways that give rise to iPMF following prolonged reductions in phrenic neural activity and found that these same mechanisms do not give rise to iPMF following intermittent reductions in phrenic neural activity. Since many clinical disorders are characterized by recurrent, brief reductions in respiratory neural activity, our specific goal in the present project period is to investigate cellular mechanisms that give rise to iPMF following intermittent phrenic neural hypoactivity and begin studies investigating the role for iPMF in the control of breathing. Our working model is that intermittent reductions in phrenic synaptic inputs stimulates retinoic acid synthesis in the phrenic motor nucleus, which activates RAR? receptors in phrenic motor neurons to increase activity of the atypical PKC isoform PKC? and give rise to iPMF (Aim 1). We hypothesize that spinal mechanisms that give rise to iPMF result in a lowering of the CO2 threshold for phrenic inspiratory activity (Aim 2). We propose that induction of a distinct form of plasticity known as phrenic long-term facilitation (pLTF) by concurrent exposure to hypoxia undermines iPMF due to an NMDA receptor-mediated constraint of the cellular pathways giving rise to iPMF (Aim 3). Our fundamental hypothesis is that iPMF is a compensatory mechanism that detects and corrects reductions in phrenic motor output, thereby preventing apneas and hypopneas (Aim 4). A detailed understanding of cellular cascades giving rise to and constraining iPMF is essential to understand the physiological role of this highly novel form of plasticity, and?importantly?to identify promising therapeutic targets for pharmacological interventions to treat respiratory control disorders characterized by recurrent disruptions in respiratory neural activity, such as central sleep apnea.
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1 |