Monday, June 23, 2025 6/23/2025

Enhancing Respiratory Motor Function after Spinal Cord Injury

Award Number: R01HL146114
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Enhancing Respiratory Motor Function after Spinal Cord Injury - ABSTRACT The proposed studies focus on the role of BDNF/TrkB signaling in promoting phrenic motor neuron (PhMN) survival and pre- and postsynaptic neuroplasticity to enhance functional recovery after cervical spinal cord injury (cSCI). We will leverage our extensive experience using two well-established models of incomplete cSCI, i.e., C2 hemisection - C2SH and C4 contusion injury - C4CI to explore neuroplasticity at PhMNs. We will also bring years of experience examining diaphragm muscle (DIAm) motor unit physiology, recognizing the importance of PhMN size in the recruitment of DIAm motor units. Stratifying the effects of BDNF/TrkB signaling on pre- and postsynaptic neuroplasticity in PhMNs of varying size is conceptually innovative and provides valuable mechanistic insight. The “Size Principle” is a key concept in neuromotor control physiology, but until now it has been difficult to directly include motor neuron size as a critical variable. We hypothesize that there are size- dependent differences in BDNF/TrkB signaling effects on pre- and postsynaptic neuroplasticity after cSCI. The proposed studies will provide novel information about PhMN neuroplasticity underlying functional recovery of inspiratory and post-inspiratory DIAm activity that will inform development of novel therapeutic approaches to enhance recovery of DIAm function in patients with incomplete cSCI. The proposed studies will utilize a comprehensive array of innovative techniques, many developed in our lab. In all 3 specific aims, we will examine the effects of modulating BDNF/TrkB signaling using a gain/loss of function approach utilizing intrathecal BDNF or TrkB-Fc treatment and a novel TrkBF616A rat with a 1NMPP1 sensitive knock-in allele that rapidly and selectively inhibits TrkB kinase activity. In Aim 1, we will use high resolution confocal imaging to explore the role of BDNF/TrkB signaling on the recovery of Glu and Gly/GABA presynaptic terminals on retrogradely labeled PhMNs of varying size following C2SH. In Aim 2, we will employ a novel RNAscope in situ hybridization technique to simultaneously explore changes in NMDA, Gly and GABAA receptor mRNA expression in PhMNs of varying size. In Aim 3, we will examine the neuroprotective effects (PhMN survival) of BDNF/TrkB signaling following C4CI. In addition, we will examine the effect of BDNF/TrkB signaling on Glu and Gly/GABA synaptic input and NMDA, Gly and GABAA receptor mRNA expression (pre- and postsynaptic neuroplasticity) in surviving PhMNs above (i.e., C3) and below (i.e., C5) the C4CI injury.


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: 2025 ( Subtotal = $698,016 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	000	7	4/18/2025	NON-COMPETING CONTINUATION	$698,016
														Subtotal = $698,016

Issue Date FY: 2024 ( Subtotal = $760,062 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	001	6	3/21/2024	NON-COMPETING CONTINUATION	$698,016
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	002	6	6/22/2024	NON-COMPETING CONTINUATION	$62,046
2024	2022	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	000	4	2/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $760,062

Issue Date FY: 2023 ( Subtotal = $775,574 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	001	5	3/20/2023	COMPETING CONTINUATION	$764,041
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	003	5	9/1/2023	COMPETING CONTINUATION	$0
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	002	5	4/18/2023	COMPETING CONTINUATION	$11,533
2023	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	000	4	3/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $775,574

Issue Date FY: 2022 ( Subtotal = $578,205 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	000	4	12/23/2021	NON-COMPETING CONTINUATION	$520,384
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$57,821
														Subtotal = $578,205

Issue Date FY: 2021 ( Subtotal = $578,205 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$57,821
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	000	3	1/4/2021	NON-COMPETING CONTINUATION	$520,384
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	National Center on Sleep Disorders Research	002	3	9/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $578,205

Issue Date FY: 2020 ( Subtotal = $578,205 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Lung Diseases Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$28,909
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Lung Diseases Research	000	2	1/9/2020	NON-COMPETING CONTINUATION	$549,296
														Subtotal = $578,205

Issue Date FY: 2019 ( Subtotal = $578,205 )
2019	2019	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Lung Diseases Research	000	1	12/31/2018	NEW	$578,205
														Subtotal = $578,205

Grand Total All Awards = $4,546,472

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Enhancing Respiratory Motor Function after Spinal Cord Injury

Award Number: R01HL146114

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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