Wednesday, December 31, 2025 12/31/2025

Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity

Award Number: R01HL148030
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/19/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity - ABSTRACT Plasticity is a hallmark of the neural system controlling breathing. One extensively studied form of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output after acute intermittent hypoxia (AIH). Multiple, distinct cellular mechanisms contribute to AIH-induced pLTF. Unfortunately, our understanding of how these mechanisms are regulated is limited. Two distinct mechanisms of AIH-induced phrenic motor facilitation (pMF) are known as the Q and S pathways. The Q pathway requires phrenic motor neuron 5-HT2 receptor activation, whereas the S pathway is initiated by phrenic motor neuron 5-HT7 receptors. Q and S pathway co-activation elicits powerful cross-talk inhibition; in fact, equal Q and S pathway activation cancels pMF expression. With moderate AIH (mAIH), the Q pathway dominates but is constrained by S pathway inhibition; S pathway inhibition releases this “brake,” doubling mAIH-induced pLTF. Repetitive AIH (rAIH) preconditioning enhances mAIH-induced pLTF through unknown mechanisms. This property is essential in our translational efforts to harness rAIH as a treatment to improve breathing in people with cervical spinal injury or neuromuscular disease. The fundamental goal of this proposal is to understand how these cumulative rAIH benefits arise. Our central hypothesis is that rAIH minimizes Q-S pathway cross-talk interactions, enabling both to contribute to AIH-induced phrenic motor plasticity. AIH-induced phrenic motor plasticity exhibits profound age-dependent sexual dimorphism. However, we know essentially nothing concerning how age and sex alter differentially affect pMF mechanisms, or their response to rAIH preconditioning. Thus, we will compare Q and S pathway interactions in young (3 month) and middle-aged (12 month) female vs male rats (when sexual dimorphisms are greatest). We will also investigate differential rAIH preconditioning effects on diaphragm LTF in unanesthetized young and middle-aged female vs male rats. Increased understanding of age and sex effects in normal rats will establish the “ground rules” for translation to clinical disorders that afflict men and women of different ages. We propose a working cellular model of rAIH-enhanced pLTF based on literature and exciting preliminary data. Based on this model, we propose four specific aims to test the hypotheses that rAIH preconditioning: 1) decreases Q and S pathway cross-talk inhibition, enabling contributions from both (Aim 1); and 2) strengthens the Q pathway to pMF by increasing the expression of key pathway molecules (Aim 2). Since AIH-induced pLTF exhibits profound age-dependent sexual dimorphisms, we will test the hypotheses that: 1) the Q and S pathways to pMF are differentially affected by age and the estrus cycle female rats (Aim 3); and 2) age and sex are key determinants of rAIH-enhanced diaphragm motor plasticity (Aim 4). These studies will greatly advance our understanding of rAIH-enhanced phrenic motor plasticity, and accelerate our ability to harness rAIH as a therapeutic modality to treat devastating clinical disorders that compromise breathing and threaten life itself.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$8,128 )
2026	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	National Center on Sleep Disorders Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	-$8,128
														Subtotal = -$8,128

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	National Center on Sleep Disorders Research	000	4	6/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $593,959 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	National Center on Sleep Disorders Research	000	4	8/18/2022	NON-COMPETING CONTINUATION	$593,959
														Subtotal = $593,959

Issue Date FY: 2021 ( Subtotal = $593,959 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	National Center on Sleep Disorders Research	000	3	7/29/2021	NON-COMPETING CONTINUATION	$593,959
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	National Center on Sleep Disorders Research	001	3	9/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $593,959

Issue Date FY: 2020 ( Subtotal = $593,959 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Lung Diseases Research	000	2	7/8/2020	NON-COMPETING CONTINUATION	$593,959
														Subtotal = $593,959

Issue Date FY: 2019 ( Subtotal = $593,959 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Lung Diseases Research	000	1	7/18/2019	NEW	$593,959
														Subtotal = $593,959

Grand Total All Awards = $2,367,708

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Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity

Award Number: R01HL148030

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/19/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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