The proposed studies exploit exciting new developments in neuroplasticity to enhance recovery of respiratory function following cervical spinal cord injury (SCI). There are about 12,000 new cases of SCI in the United States each year, with nearly 500,000 people affected. Most SCI's are incomplete with some sparing of spinal cord pathways. The number of injuries involving the cervical spinal cord is increasing, with resulting impairments of rhythmic phrenic nerve activity and paralysis of the diaphragm muscle. Inability to generate expulsive behaviors as well as long-term mechanical ventilation needed to support such SCI patients is associated with elevated infectious, morbidity and mortality rates. In recent studies supported by this grant, we found that the neurotrophin brain-derived neurotrophic factor (BDNF) acting through the full-length high affinity tropomyosin related kinase receptor subtype B (TrkB.FL) plays an important role in neuroplasticity and recovery of phrenic activity following SCI. This proposal will exploit a multi-pronged approach to gain mechanistic insight into the effects of BDNF/TrkB.FL signaling on: 1) strengthening of spared synaptic inputs to phrenic motoneurons, and 2) enhancing motoneuron survival post-SCI. Our working hypothesis is that increasing BDNF/TrkB.FL signaling in phrenic motoneurons enhances functional recovery of rhythmic phrenic activity after cervical SCI. Three complementary models of cervical SCI that differentially impact respiratory function will be used in combination with targeted intrapleural AAV-mediated delivery of TrkB.FL to phrenic motoneurons, localized transplantation of adult-derived mesenchymal stem cells engineered to release BDNF and a chemical-genetic approach using a TrkB knock-in mouse that permits rapid and selective inhibition of TrkB kinase activity in gain-of-function/loss-of-function study design. Phrenic motoneuron expression of excitatory glutamate and serotonin receptors correlates with the time course of functional recovery after SCI, and thus we hypothesize that BDNF/TrkB.FL acts on phrenic motoneurons to enhance recovery of rhythmic phrenic activity via expression of specific glutamate and serotonin receptor subtypes.
Three specific aims are proposed: 1) To determine whether functional recovery of rhythmic phenic activity after SH is enhanced by targeting increased BDNF/TrkB.FL signaling to phrenic motoneurons;2) To determine the role of glutamatergic and serotonergic neurotransmission in the BDNF/TrkB.FL mediated recovery of rhythmic phrenic activity after SH;and 3) To determine the role of enhanced phrenic motoneuron BDNF/TrkB.FL signaling on motoneuron survival and functional recovery following mid-cervical contusion injury. We will assess phrenic responses across a range of motor behaviors to maximize functional gains associated with recovery. Our long-term goal is to develop an effective, targeted therapy to increase BDNF/TrkB.FL signaling in phrenic motoneurons to strengthen spared synaptic inputs to phrenic motoneurons and promote motoneuron survival, thereby enhancing functional recovery following SCI.

Public Health Relevance

Spinal cord injury is a devastating problem that affects about 500,000 people in the United States, with 12,000 new cases each year. The diaphragm muscle is the most important inspiratory muscle and it is paralyzed or seriously impaired in many cases of spinal cord injury. The proposed studies will use exciting, new information on the mechanisms underlying recovery of respiratory function to explore novel therapies for patients with spinal cord injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Laposky, Aaron D
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Mayo Clinic, Rochester
United States
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Khurram, Obaid U; Fogarty, Matthew J; Rana, Sabhya et al. (2018) Diaphragm muscle function following mid-cervical contusion injury in rats. J Appl Physiol (1985) :
Mantilla, Carlos B; Zhan, Wen-Zhi; Gransee, Heather M et al. (2018) Phrenic motoneuron structural plasticity across models of diaphragm muscle paralysis. J Comp Neurol 526:2973-2983
Gonzalez Porras, Maria A; Sieck, Gary C; Mantilla, Carlos B (2018) Impaired Autophagy in Motor Neurons: A Final Common Mechanism of Injury and Death. Physiology (Bethesda) 33:211-224
Jimenez-Ruiz, Federico; Khurram, Obaid U; Zhan, Wen-Zhi et al. (2018) Diaphragm muscle activity across respiratory motor behaviors in awake and lightly anesthetized rats. J Appl Physiol (1985) 124:915-922
Fogarty, Matthew J; Mantilla, Carlos B; Sieck, Gary C (2018) Breathing: Motor Control of Diaphragm Muscle. Physiology (Bethesda) 33:113-126
Gransee, Heather M; Gonzalez Porras, Maria A; Zhan, Wen-Zhi et al. (2017) Motoneuron glutamatergic receptor expression following recovery from cervical spinal hemisection. J Comp Neurol 525:1192-1205
Hernandez-Torres, Vivian; Gransee, Heather M; Mantilla, Carlos B et al. (2017) BDNF effects on functional recovery across motor behaviors after cervical spinal cord injury. J Neurophysiol 117:537-544
Rana, Sabhya; Sieck, Gary C; Mantilla, Carlos B (2017) Diaphragm electromyographic activity following unilateral midcervical contusion injury in rats. J Neurophysiol 117:545-555
Khurram, Obaid U; Sieck, Gary C; Mantilla, Carlos B (2017) Compensatory effects following unilateral diaphragm paralysis. Respir Physiol Neurobiol 246:39-46
Martínez-Gálvez, Gabriel; Zambrano, Juan M; Diaz Soto, Juan C et al. (2016) TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury. Exp Neurol 276:31-40

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