2013 — 2017 |
Elfar, John |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Erythropoietin For Neuroregeneration @ University of Rochester
DESCRIPTION (provided by applicant): Peripheral nerve injuries represent a major public health problem, seen frequently in patients admitted to level I trauma centers and in as many as 30% of individuals with traumatic brain injuries. A primary goal of intervention in this arena is t hasten recovery so as to restore function as rapidly as possible. Progress towards this goal, however, has been limited. Interestingly, we recently discovered that systemic erythropoietin (EPO) administration speeds functional recovery after experimental crush injury to the sciatic nerve, even when EPO is administered one week after injury. These findings have already led to clinical studies being initiated overseas. Understanding how EPO induces this beneficial effect would enable us to design conditions and dosing strategies that can optimize its therapeutic effects; this is the goal of th3e studies proposed in this application. In the first Specific Aim, we will address the question of whether local delivery of EPO, rather than systemic delivery, will enable us to further enhance recovery and thus set the stage for the development of innovative local delivery methods to enhance/induce repair. The pleiotropic multi-organ effects of EPO, coupled with the surgical and medical focus for local treatment for local traumatic injury argues for a local application of this potent pharmacologic bio-modulator. This, in effect, focuses the effect of EPO directly at the site of injury, eliminating secondary effects and enabling the optimization of treatment in a clinically relevant and targeted manner. In the second Specific Aim, we will test the hypothesis that at least part of the mechanism of EPO action derives from beneficial effects on Schwann cells, the cells that support the function of peripheral nerves by myelinating the axons that run through these nerves. Overall, the identification of target cell(s) of EPO action will better enable us to determine how benefit occurs. In this Specific Aim, we will also begin teasing apart the underlying signaling that supports the impact of EPO, providing a basis for envisioning adjuvant therapies that focus on manipulating the key signaling players in the EPO receptor pathway. The above Specific Aims will represent the research training component of the proposed program to support the transition of Dr. John Elfar MD, a clinician/surgeon who is expanding his academic role to the clinician scientist track. The proposed research training plan is positioned on the backdrop of a robust mentoring and didactic training program that collectively represents a multi- faceted training environment aimed at ensuring successful career transition for Dr. Elfar.
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0.958 |
2021 |
Elfar, John |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Single Dose Pharmaco-Diagnostic For Peripheral Nerve Continuity After Trauma @ Pennsylvania State Univ Hershey Med Ctr
Abstract Nerve injury can affect anyone and carries consequences that last forever, and traumatic peripheral nerve injury (TPNI) can result from settings as diverse as battlefield or motor vehicle trauma, to iatrogenic injury from surgical treatments of other serious conditions. For other tissue types, the prognosis and treatment plan are straightforward. However, when nerves fail, doctors have few tools to help guide the treatment plan and patients forever remember their experiences with pain and paralysis. If nerve injuries can happen from many causes, what is the determinant that most predicts a good outcome? The answer is nerve continuity. A nerve that has been severed, say by a bullet will never heal without surgical repair and yet, that same nerve, grazed by the bullet, or caught in the shockwave of a passing bullet, is indistinguishable from the nerve cut by the bullet. Both nerves do not work, and yet the latter, unsevered nerve is best left to recover on its own without surgery. Two types of nerve injury exist, both yield nerves that are equally dysfunctional and yet we need to surgically repair one whereas surgery is detrimental to the other. No test exists to tell these nerves apart until weeks have passed after the injury. After weeks have passed, we use electrodiagnostics (EDX) to tell which nerves were severed. This is the state of the art in TPNI diagnosis. Because continuity of the nerve is itself impossible to define for weeks after injury, the current standard treatment is waiting for spontaneous recovery in most patients we guess do not have a severed nerve. In every field of medicine, there are nerve injuries monitored in this way - without tools for definitive diagnosis, based on our clinical suspicion. We recently discovered that a current, FDA-approved drug (4-aminopyridine, 4AP), has the previously unknown effect of immediately allowing diagnosis of traumatically paralyzed nerves. Small doses can distinguish the severed nerve, which requires immediate surgery, from the non-severed nerve, which can be safely monitored. This novel property of 4AP, a drug already used in humans may be explored while we wait for function to spontaneously return. Based on our preliminary data, we intend to repurpose 4AP to diagnose nerve discontinuity instead of just guessing if the nerve is severed and hoping for recovery. We want to try 4AP in patients who have nerve injury where we cannot tell if the nerve was severed or not. We obtained FDA approval for a trial of 4AP in humans to investigate nerve continuity and have institutional IRB approval to proceed. We want to test 4AP in humans with TPNI in a novel way: As a pharmacologic diagnostic, where the results of a challenge with the drug reveal something about the underlying nerve continuity. With the knowledge gained from this trial, we hope to provide solid information that can confirm or refute clinical guesswork on the critical issue of nerve continuity.
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0.936 |