Recovery of Breathing Function After Spinal Cord Injury
In this research project, our lab is studying the mechanisms underlying neural control of respiratory muscles. This research is needed to find ways to restore the full complement of respiratory function after spinal cord injury.
Injury to the upper segments of the cervical spinal cord often results in complete or partial paralysis of respiratory muscles, including the diaphragm muscle. Impaired respiratory muscle function frequently requires ventilatory support for patients and is associated with higher morbidity and mortality rates.
Our research uses new information about the mechanisms underlying recovery of respiratory function to explore novel therapies for patients with spinal cord injury.
Led by Dr. Mantilla, our team showed that recovery of diaphragm muscle activity is enhanced by promoting the effect of brain-derived neurotrophic factor (BDNF) at phrenic motor neurons. For example, intrathecal BDNF treatment enhances functional recovery of rhythmic diaphragm muscle activity after spinal cord injury.
Unfortunately, intrathecal BDNF treatment is associated with significant negative adverse effects that preclude its use. As an alternative, we used locally implanted mesenchymal stem cells that are genetically engineered to produce BDNF. We combined this with a novel targeted approach to increase expression of tropomyosin related kinase receptor (TrkB) in phrenic motor neurons using an adeno-associated virus, thereby promoting functional recovery after spinal cord injury.
Recovery of respiratory function after spinal cord injury
Our research exploits exciting new developments in neuroplasticity to enhance recovery of respiratory function after cervical spinal cord injury.
Most spinal cord injuries 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.
Our working hypothesis is that increasing brain-derived neurotrophic factor-tropomyosin related kinase receptor (BDNF-TrkB) signaling in phrenic motor neurons enhances functional recovery of rhythmic phrenic activity after cervical spinal cord injury. Dr. Mantilla is assessing phrenic responses across a range of motor behaviors to maximize functional gains associated with recovery.
This research project takes a multipronged approach to gain mechanistic insight into the effects of BDNF-TrkB signaling on strengthening spared synaptic inputs to phrenic motor neurons and enhancing motor neuron survival after spinal cord injury.
Our long-term goal is to develop an effective, targeted therapy to increase BDNF-TrkB signaling in phrenic motor neurons to strengthen spared synaptic inputs to phrenic motoneurons and promote motoneuron survival, thereby enhancing functional recovery after spinal cord injury.