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Respiratory interneuron circuit plasticity: promoting recovery of diaphragm function after spinal cord injury

Award Number: R01NS079702
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2013
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Respiratory interneuron circuit plasticity: promoting recovery of diaphragm function after spinal cord injury - Project Summary / Abstract (30-line maximum) Spinal cord interneurons (INs) play indispensable roles in CNS circuit connectivity and function. Importantly, spinal IN populations are centrally involved in plasticity mechanisms responsible for mediating the limited degree of functional recovery that can occur spontaneously after spinal cord injury (SCI). Therefore, critical questions that need to be addressed are: Can therapeutic interventions further recruit these spinal cord INs into remodelled circuits to robustly restore lost function following SCI? If so, by which modes of circuit plasticity can this spinal cord IN recruitment occur? To address this highly important topic in this R01 Renewal application, we aim to examine whether therapeutically stimulating axon regeneration can promote respiratory circuit plasticity via the formation of pre-phrenic IN (PP-IN) relay circuits to drive recovery of diaphragm function after cervical SCI. A majority of SCI cases occur in the cervical spinal cord, resulting in persistent diaphragmatic respiratory dysfunction that is associated with mortality, dependence on mechanical ventilation, a host of morbidities such as respiratory infections, and greatly reduced quality of life. Diaphragm is directly controlled by phrenic motor neurons (PhMNs) located at cervical spinal cord levels C3, C4 and C5. PhMNs are monosynaptically activated by supraspinal brainstem neurons located in rostral Ventral Respiratory Group (rVRG). Cervical SCI results in the axotomy of descending rVRG fibers, denervation and silencing of spared PhMNs, and diaphragm paralysis. We have demonstrated that systemic administration of a blood brain barrier-permeable PTEN antagonist peptide (PAP) can regenerate rVRG axons after cervical SCI, resulting in significant restoration of diaphragm function. Excitingly, our findings suggest that PAP-induced rVRG axon regeneration is promoting a substantial portion this diaphragm recovery via formation of polysynaptic PP-IN relay circuitry. Specifically, we hypothesize that intersegmental PP-INs can be recruited to relay bulbospinal input from regenerating rVRG axons to PhMNs. In Aim 1 studies, we will determine whether selectively silencing C3-to-C5 projecting intersegmental PP- INs impacts recovery of diaphragm function stimulated by PAP-induced rVRG axon regeneration after C2 hemisection SCI. To do so, we will use an innovative dual-viral vector chemogenetic silencing approach, coupled with monosynaptic and polysynaptic retrograde and anterograde rVRG / PP-IN / PhMN circuit tracing. In Aim 2, we will determine whether therapeutically stimulating regeneration of C1-to-C5 projecting PP-IN axons across a SCI lesion promotes diaphragm recovery after C2 hemisection, again using a chemogenetic silencing strategy. In Aim 3, we will extend this work to the more clinically-associated cervical contusion SCI model to begin to assess the translational potential of targeting intersegmental PP-IN plasticity to promote respiratory recovery. In this innovative and highly-significant project, we will: (1) determine whether spinal cord IN populations can be beneficially recruited into new neural circuits in response to therapeutic stimulation of axon regeneration; and (2) uncover PP-IN plasticity mechanisms capable of promoting respiratory recovery following cervical SCI.


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 = $542,250 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	13	6/18/2025	NON-COMPETING CONTINUATION	$542,250
2025	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	2/12/2025	COMPETING CONTINUATION	$127,516
2025	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/12/2025	NON-COMPETING CONTINUATION	-$127,516
														Subtotal = $542,250

Issue Date FY: 2024 ( Subtotal = $527,158 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	6/21/2024	NON-COMPETING CONTINUATION	$527,158
														Subtotal = $527,158

Issue Date FY: 2023 ( Subtotal = $568,743 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	4/27/2023	COMPETING CONTINUATION	$568,743
2023	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $568,743

Issue Date FY: 2022 ( Subtotal = $408,077 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/30/2022	NON-COMPETING CONTINUATION	$408,077
														Subtotal = $408,077

Issue Date FY: 2021 ( Subtotal = $409,181 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/17/2021	NON-COMPETING CONTINUATION	$409,181
														Subtotal = $409,181

Issue Date FY: 2020 ( Subtotal = $410,258 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/4/2020	NON-COMPETING CONTINUATION	$410,258
														Subtotal = $410,258

Issue Date FY: 2019 ( Subtotal = $415,113 )
2019	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/14/2019	NON-COMPETING CONTINUATION	$415,113
														Subtotal = $415,113

Issue Date FY: 2018 ( Subtotal = $436,517 )
2018	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	7/31/2018	COMPETING CONTINUATION	$65,533
2018	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/13/2018	COMPETING CONTINUATION	$436,517
2018	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	7/31/2018	NON-COMPETING CONTINUATION	-$65,533
2018	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/12/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $436,517

Issue Date FY: 2017 ( Subtotal = $336,385 )
2017	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/7/2017	NON-COMPETING CONTINUATION	$33,640
2017	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/17/2017	NON-COMPETING CONTINUATION	$302,745
														Subtotal = $336,385

Issue Date FY: 2016 ( Subtotal = $336,377 )
2016	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/29/2016	EXTENSION WITH OR WITHOUT FUNDS	$336,377
														Subtotal = $336,377

Issue Date FY: 2015 ( Subtotal = $341,055 )
2015	2015	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/29/2015	NON-COMPETING CONTINUATION	$341,055
														Subtotal = $341,055

Issue Date FY: 2014 ( Subtotal = $336,240 )
2014	2014	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/20/2014	NON-COMPETING CONTINUATION	$305,672
2014	2014	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/10/2014	NON-COMPETING CONTINUATION	$30,568
														Subtotal = $336,240

Issue Date FY: 2013 ( Subtotal = $352,761 )
2013	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/19/2013	NEW	$352,761
														Subtotal = $352,761

Grand Total All Awards = $5,420,115

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Respiratory interneuron circuit plasticity: promoting recovery of diaphragm function after spinal cord injury

Award Number: R01NS079702

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2013

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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