(30-line maximum). A majority of traumatic spinal cord injury (SCI) cases occur in the cervical spinal cord, resulting in persistent diaphragmatic respiratory dysfunction that is associated with mortality, a host of morbidities such as respiratory infections, and greatly reduced quality of life. Diaphragm is directly controlled by phrenic motor neurons (PMNs) located at levels C3-5. PMNs are mono-synaptically activated by supraspinal brainstem neurons located in the rostral Ventral Respiratory Group (rVRG). Cervical SCI results in axotomy of descending rVRG fibers, denervation and silencing of spared PMNs, and partial-to-complete hemi-diaphragm paralysis. In this Competing Continuation (?Renewal?) application, we aim to promote reconnection of rVRG-PMN- diaphragm circuitry in a rat model of cervical SCI, a critically important therapeutic goal for individuals with SCI. We developed inhibitory peptides against PTEN (phosphatase and tensin homolog: a central inhibitor of neuron-intrinsic axon growth potential) and PTP? (protein tyrosine phosphatase-sigma: an axonally-expressed receptor that mediates the neuron-extrinsic axon growth inhibitory effects of chondroitin sulfate proteoglycans). Our exciting preliminary findings show that systemic delivery of these peptides each result in robust ? but partial ? recovery of diaphragm function in the C2 hemisection model of SCI. These initial studies also provide compelling data suggesting that PTEN and PTP? inhibition may promote recovery via different modes of rVRG axon growth: (1) robust regeneration of injured ipsilateral rVRG axons with PTEN inhibition; (2) extensive sprouting of spared contralateral rVRG axons into the PMN pool (ipsilateral to the lesion) with PTP? inhibition. Importantly, we do not understand which modes of axon growth can promote recovery of diaphragm function after SCI, which significantly limits ability to develop targeted therapies. To address this critical issue, we will use chemogenetic DREAAD manipulations to selectively-silence defined neuronal populations involved in respiratory control in order to determine the mode(s) of circuit re-connectivity that causally drive recovery in response to PTEN and PTP? manipulation. We will target PTEN and PTP? with systemic delivery of inhibitory peptides and rVRG neuron-specific transduction with AAV-shRNA. We will compliment this approach using an array of cutting-edge functional and axonal/synaptic tracing methods to assess rVRG-PMN circuit plasticity. We hypothesize that stimulating (1) regeneration of injured rVRG axons, (2) sprouting of spared fibers originating in contralateral rVRG, and (3) synaptic connectivity of these growing rVRG axons with PMNs (located caudal to the lesion) will causally promote recovery of diaphragmatic respiratory function following cervical SCI. We also hypothesize that the combination of rVRG axon regeneration and sprouting of spared rVRG fibers will promote robust diaphragm recovery in the clinically-associated cervical contusion SCI model. We will acquire an in-depth understanding of how modulating axon growth inhibition can induce rVRG- PMN circuit plasticity and, importantly, which modes of connectivity promote diaphragm recovery after SCI.

Public Health Relevance

/ Relevance A majority of human spinal cord injury (SCI) cases occur in the cervical region, resulting in persistent respiratory dysfunction that is associated with mortality, morbidities such as respiratory infections, and greatly reduced patient quality of life. Cervical SCI disrupts the neural circuitry that controls the diaphragm (the major muscle of inspiratory breathing); however, axon regeneration and consequent restoration of this critical circuitry do not occur following SCI. In an animal model of cervical SCI, we will test strategies aimed at promoting recconection of this neural circuitry for restoring diaphragmatic respiratory function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Jakeman, Lyn B
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Thomas Jefferson University
Schools of Medicine
United States
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Ghosh, Biswarup; Wang, Zhicheng; Nong, Jia et al. (2018) Local BDNF Delivery to the Injured Cervical Spinal Cord using an Engineered Hydrogel Enhances Diaphragmatic Respiratory Function. J Neurosci 38:5982-5995
Goulão, Miguel; Ghosh, Biswarup; Urban, Mark W et al. (2018) Astrocyte progenitor transplantation promotes regeneration of bulbospinal respiratory axons, recovery of diaphragm function, and a reduced macrophage response following cervical spinal cord injury. Glia :
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Urban, Mark W; Ghosh, Biswarup; Strojny, Laura R et al. (2018) Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI. Exp Neurol 303:108-119
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Charsar, Brittany A; Urban, Mark W; Lepore, Angelo C (2017) Harnessing the power of cell transplantation to target respiratory dysfunction following spinal cord injury. Exp Neurol 287:268-275
Goulão, Miguel; Lepore, Angelo C (2016) iPS cell transplantation for traumatic spinal cord injury. Curr Stem Cell Res Ther 11:321-8
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Nicaise, Charles; Mitrecic, Dinko; Falnikar, Aditi et al. (2015) Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury. World J Stem Cells 7:380-98
Falnikar, Aditi; Li, Ke; Lepore, Angelo C (2015) Therapeutically targeting astrocytes with stem and progenitor cell transplantation following traumatic spinal cord injury. Brain Res 1619:91-103

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