Dr. Windebank's research team in the Regenerative Neurobiology Lab is investigating different causes of neurodegeneration in order to encourage nerve regeneration where possible, as well as developing clinical trials that use cell-based therapies to treat neurological disease. Four main areas are currently being investigated.
Chemotherapy-induced peripheral neuropathy (CIPN)
Chemotherapy agents used to treat cancer may damage the nervous system. Peripheral neuropathy is a common dose-limiting side effect.
The lab's research team has studied the mechanism of cisplatin neurotoxicity for a number of years. Cisplatin binds nuclear and mitochondrial DNA (mtDNA) in cancer cells and rat dorsal root ganglion (DRG) neurons inducing DNA damage and apoptosis.
The team's studies found mtDNA binding inhibits mtDNA replication and mtRNA transcription leading to mitochondrial disassembly. Our lab has developed a novel model of cisplatin-induced neurotoxicity in Drosophila melanogaster using survival and behavioral assays.
The drosophila model system provides a powerful tool to study basic cellular mechanisms using genetic approaches. The lab is using genetic epidemiology, high-density genome sequencing and epigenetic approaches to study CIPN in patients and to test hypotheses in model systems.
Peripheral nerve repair and regeneration (PNR)
Peripheral nerve repair and regeneration research focuses on developing synthetic nerve conduits as an alternative to autologous nerve graft to repair segmental nerve defects. A first-generation polycaprolactone fumarate (PCLF) nerve conduit is currently in clinical trial.
Various electrical stimulation paradigms are being tested using both in vitro and in vivo experimental systems. Other aspects of the research efforts include examining the roles of growth factors, stem cells and conditions such as ischemia, fibrosis and delayed repair on nerve regeneration and functional recovery.
Spinal cord injury (SCI) and repair
Spinal cord injury results in permanent injury of axons, neurons and glial cells. Regrowth of axons is essential to repair and functional recovery of the spinal cord. Tissue destruction with cysts and gliosis at the site of injury forms a barrier to regeneration.
In the lab, we are using tissue engineering with biodegradable polymer scaffolds (PLGA, PCLF, OPF) loaded with different growth-promoting cells (Schwann cells, neural progenitor cells, mesenchymal stem cells) and different growth factors (GDNF, NT3, BDNF) to bridge the gap. This is being combined with electrical stimulation and exercise regimens to promote axonal regeneration and functional restoration in the spinal cord of rats and mice, eventually for future use in patients.
The lab's research team is investigating the effects of exercise training and local delivery of steroids on the axon regeneration and functional recovery of animals with spinal cord injuries. In addition to the transection model, we developed hemisection and contusion models in studies of the SCI mechanisms.
Therapy for amyotrophic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a rapidly progressive, uniformly fatal neurodegenerative disease. It is characterized by the loss of motor neurons in the spinal cord, brainstem and cerebral cortex, leading to a decline in muscular function. It eventually results in weakness, speech deficits and difficulty swallowing. ALS is almost always fatal within two to three years.
Mensenchymal stem cells (MSCs) are multipotent, self-renewing cells with the potential for tissue regeneration. These cells also have the potential for gene delivery and to transdifferentiate into cells of mesodermal origin. MSCs can be used as vectors of cytokines and trophic factors to prevent cell death, tissue inflammation and damage. The lab is developing h-MSCs as a delivery platform for therapeutic factors in ALS where they may have an intrinsic therapeutic effect.