Research

Dr. Windebank's research team in the Regenerative Neurobiology Lab is investigating different causes of neurodegeneration to encourage nerve regeneration where possible. The lab also is developing clinical trials that use cell-based therapies to treat neurological diseases. Four main areas are being investigated.

Organotypic rat dorsal root ganglion culture. Chemotherapy-induced peripheral neuropathy

A cluster of nerve cells (in light blue) in the culture send out nerve fibers on a collagen surface.

Chemotherapy-induced peripheral neuropathy

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 several years. Cisplatin binds nuclear and mitochondrial DNA in cancer cells and rat dorsal root ganglion neurons, inducing DNA damage and apoptosis.

The team's studies found that mitochondrial DNA binding inhibits mitochondrial DNA replication and mitochondrial DNA transcription, leading to mitochondrial disassembly. The 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 chemotherapy-induced peripheral neuropathy in patients and test hypotheses in model systems.

Rat hindlimb muscle tissue stained for different fiber types. Cross section of a rat hindlimb muscle

This photo illustrates a cross section of muscle tissue stained with different colors to illustrate different muscle fiber types. Immunoenzyme staining revealed the mosaic pattern of varying myofiber types, including type 1, type 2B, type 2A, type 2X, type 2A/X and type 2B/X, on that cross section.

Peripheral nerve repair and regeneration

Peripheral nerve repair and regeneration research focuses on developing synthetic nerve conduits as an alternative to an autologous nerve graft to repair segmental nerve defects. A first-generation polycaprolactone fumarate nerve conduit is 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.

These are dorsal root ganglion neurons growing on a polymer scaffold used for repair after spinal cord injury. Dorsal root ganglion neurons and their axons growing on a patterned biomaterial surface

The image illustrates single nerve cells (brown) growing on a patterned biomaterial surface.

Spinal cord injury and repair

Spinal cord injury results in permanent injury of axons, neurons and glial cells. Regrowth of axons is essential to the repair and functional recovery of the spinal cord. Tissue destruction with cysts and gliosis at the site of injury forms a barrier to regeneration.

The lab is using tissue engineering with biodegradable polymer scaffolds (PLGA, PCLF and OPF) loaded with different growth-promoting cells (Schwann cells, neural progenitor cells, mesenchymal stem cells) and different growth factors (GDNF, NT3 and BDNF) to bridge the gap. These scaffolds are 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 axon regeneration and functional recovery of animals with spinal cord injuries. In addition to the transection model, the lab developed hemisection and contusion models in studies of spinal cord injury mechanisms.

Illustration of gene delivery by viruses. Therapy for amyotrophic lateral sclerosis

This illustration shows gene delivery (blue spirals) by viral particles.

Therapy for amyotrophic lateral sclerosis (ALS)

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 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. Mensenchymal stem cells can be used as vectors of cytokines and trophic factors to prevent cell death, tissue inflammation and damage.

The lab is developing human mensenchymal stem cells as a delivery platform for therapeutic factors in ALS where they may have an intrinsic therapeutic effect.