The research lab of Dr. Jon Cheetham is based at the Cornell University College of Veterinary Medicine.
Values
Our culture aims to draw on a range of cognitively diverse views, which may arise from background, training, or style of thinking, to create an environment where ideas are welcome from all laboratory members and people feel comfortable sharing these ideas. We promote robust discussion and encourage others to challenge the idea rather than the person. We value innovation and detailed, diligent execution.
Goals
The goals of our lab are to understand the role of the early immune response to nerve injury, particularly the macrophage response and to use this knowledge to improve functional outcomes in peripheral nerve injury in people and after laryngeal nerve graft in dogs, horses and in people.
Funding
Agency: NIH
Title: Manipulating Macrophage Phenotype to Accelerate Recurrent Laryngeal Nerve Repair
Abstract: Vocal fold paralysis (VFP) occurs when the recurrent laryngeal nerve (RLN) is injured, most commonly during surgery of the neck. Bilateral injury to the RLN can result in potentially life-threatening airway obstruction and the need for tracheostomy. The RLN can regenerate some of its axons, but in many patients with paralysis some form of intervention is required to correct the airway obstruction and voice changes. This is most frequently achieved through reinnervation of the laryngeal muscles to restore function. Current practice is to wait 6-24 months before any intervention is performed as spontaneous recovery can occur. This delay before repair allows chronic changes in the nerve distal to the site of injury to occur and results in poor recovery. The overall goal of this proposal is to accelerate recovery after RLN injury and reduce the consequences of prolonged denervation before nerve graft. Previous work has focused mainly on events that occur late in the repair and remodeling process. Little is known about how manipulating events in the early stages of repair can be used to improve recovery. In this proposal we will evaluate how macrophage and SC function and gene expression are altered after delayed graft. We will determine gene expression, phagocytosis and migration for both cell types and determine the consequences of these changes on tissue remodeling using a variety of techniques including protein expression, the formation of a polarized microvasculature, axon extension and the number of axons reaching their target. We will then test the neuroprotective ability of an anti-inflammatory liagand to rescue the changes we have identified in delayed repair and then confirm these changes are mediated by macrophages. Finally, we test the ability of manipulation of macrophage phenotype to accelerate recovery after acute injury using a translational animal model. The ability to accelerate recovery following RLN injury, by intervening intra-operatively, would reduce the consequences of delayed repair and improve recovery for patients with VFP.
Agency: Department of Defense/Renerva LLC
Title: Injectable Gel for Restoration of Myoneural Function Following Peripheral Nerve Injury
Abstract: Renerva LLC is developing an injectable gel (“PNM”) to speed regeneration of nerves and improve functional recovery in patients who have suffered a peripheral nerve injury (PNI). PNIs including blunt and stretch traumas, deep tissue lacerations, and focal contusions are frequent cause of permanent disability from accidents and trauma. These injuries are associated with loss of function, chronic pain, or both. Surgeons performing nerve repair often give their patients very poor prognoses and little hope: nerve regeneration typically requires 3‐18 months to complete and terminal functional recovery is often less than 50%. The proposed effort will complete preclinical development and begin clinical development of PNM to treat peripheral nerve injury.
Agency: Zweig Memorial Fund
Title: Accelerating Recovery After Laryngeal Nerve Graft in Horses
Abstract: Recurrent laryngeal neuropathy (RLN) or “Roaring” is a major cause of poor athletic performance affecting 8% of racehorses and a higher percentage of sport horses. RLN produces axonal loss with demyelination and subsequent loss of cricoarytenoid dorsalis (CAD) muscle volume and inability to maintain an open airway. A surgical solution that maintains airflow by preserving CAD muscle mass and function would be associated with improved performance outcomes. A number of nerve-muscle pedicle graft techniques have been used in an attempt to restore function of this muscle. These methods transfer an innervating nerve into a small region of a denervated muscle. As they only innervate a small portion of the muscle, recovery is slow and limited and this approach has not yet gained widespread acceptance.
In this proposal we use a reinnervation approach combined with immunomodulation at the surgery site. Performing a nerve anastomosis (graft), we would take advantage of the existing architecture of the recurrent laryngeal nerve to reach all the portions of the CAD muscle, which opens the larynx. Alone, this should produce much faster recovery than nerve-muscle pedicle graft as we use the existing network of the distal RLn to guide reinnervating axons to the CAD muscle. We also intend to modulate the microenvironment at the site of nerve graft to test the hypothesis that immunomodulation will further improve the recovery time. We have used this approach in dogs and shown return of function by 60-100 days after repair. If successful in horses, this approach would be a very large improvement on existing techniques.
Our culture aims to draw on a range of cognitively diverse views, which may arise from background, training, or style of thinking, to create an environment where ideas are welcome from all laboratory members and people feel comfortable sharing these ideas. We promote robust discussion and encourage others to challenge the idea rather than the person. We value innovation and detailed, diligent execution.
Goals
The goals of our lab are to understand the role of the early immune response to nerve injury, particularly the macrophage response and to use this knowledge to improve functional outcomes in peripheral nerve injury in people and after laryngeal nerve graft in dogs, horses and in people.
Funding
Agency: NIH
Title: Manipulating Macrophage Phenotype to Accelerate Recurrent Laryngeal Nerve Repair
Abstract: Vocal fold paralysis (VFP) occurs when the recurrent laryngeal nerve (RLN) is injured, most commonly during surgery of the neck. Bilateral injury to the RLN can result in potentially life-threatening airway obstruction and the need for tracheostomy. The RLN can regenerate some of its axons, but in many patients with paralysis some form of intervention is required to correct the airway obstruction and voice changes. This is most frequently achieved through reinnervation of the laryngeal muscles to restore function. Current practice is to wait 6-24 months before any intervention is performed as spontaneous recovery can occur. This delay before repair allows chronic changes in the nerve distal to the site of injury to occur and results in poor recovery. The overall goal of this proposal is to accelerate recovery after RLN injury and reduce the consequences of prolonged denervation before nerve graft. Previous work has focused mainly on events that occur late in the repair and remodeling process. Little is known about how manipulating events in the early stages of repair can be used to improve recovery. In this proposal we will evaluate how macrophage and SC function and gene expression are altered after delayed graft. We will determine gene expression, phagocytosis and migration for both cell types and determine the consequences of these changes on tissue remodeling using a variety of techniques including protein expression, the formation of a polarized microvasculature, axon extension and the number of axons reaching their target. We will then test the neuroprotective ability of an anti-inflammatory liagand to rescue the changes we have identified in delayed repair and then confirm these changes are mediated by macrophages. Finally, we test the ability of manipulation of macrophage phenotype to accelerate recovery after acute injury using a translational animal model. The ability to accelerate recovery following RLN injury, by intervening intra-operatively, would reduce the consequences of delayed repair and improve recovery for patients with VFP.
Agency: Department of Defense/Renerva LLC
Title: Injectable Gel for Restoration of Myoneural Function Following Peripheral Nerve Injury
Abstract: Renerva LLC is developing an injectable gel (“PNM”) to speed regeneration of nerves and improve functional recovery in patients who have suffered a peripheral nerve injury (PNI). PNIs including blunt and stretch traumas, deep tissue lacerations, and focal contusions are frequent cause of permanent disability from accidents and trauma. These injuries are associated with loss of function, chronic pain, or both. Surgeons performing nerve repair often give their patients very poor prognoses and little hope: nerve regeneration typically requires 3‐18 months to complete and terminal functional recovery is often less than 50%. The proposed effort will complete preclinical development and begin clinical development of PNM to treat peripheral nerve injury.
Agency: Zweig Memorial Fund
Title: Accelerating Recovery After Laryngeal Nerve Graft in Horses
Abstract: Recurrent laryngeal neuropathy (RLN) or “Roaring” is a major cause of poor athletic performance affecting 8% of racehorses and a higher percentage of sport horses. RLN produces axonal loss with demyelination and subsequent loss of cricoarytenoid dorsalis (CAD) muscle volume and inability to maintain an open airway. A surgical solution that maintains airflow by preserving CAD muscle mass and function would be associated with improved performance outcomes. A number of nerve-muscle pedicle graft techniques have been used in an attempt to restore function of this muscle. These methods transfer an innervating nerve into a small region of a denervated muscle. As they only innervate a small portion of the muscle, recovery is slow and limited and this approach has not yet gained widespread acceptance.
In this proposal we use a reinnervation approach combined with immunomodulation at the surgery site. Performing a nerve anastomosis (graft), we would take advantage of the existing architecture of the recurrent laryngeal nerve to reach all the portions of the CAD muscle, which opens the larynx. Alone, this should produce much faster recovery than nerve-muscle pedicle graft as we use the existing network of the distal RLn to guide reinnervating axons to the CAD muscle. We also intend to modulate the microenvironment at the site of nerve graft to test the hypothesis that immunomodulation will further improve the recovery time. We have used this approach in dogs and shown return of function by 60-100 days after repair. If successful in horses, this approach would be a very large improvement on existing techniques.
© 2019 Jon Cheetham Lab | Cornell University |