Erythropoietin for Neuroregeneration

描述（由申请人提供）：周围神经损伤是一个主要的公共卫生问题，常见于I级创伤中心收治的患者和多达30%的创伤性脑损伤患者。在这一竞技场中，干预的主要目标是加速康复，以便尽可能快地恢复功能。然而，在实现这一目标方面取得的进展有限。有趣的是，我们最近发现，全身性促红细胞生成素（EPO）给药加速坐骨神经实验性挤压损伤后的功能恢复，即使在损伤后一周给予EPO。这些发现已经导致海外开始进行临床研究。了解EPO如何诱导这种有益作用将使我们能够设计可以优化其治疗效果的条件和给药策略;这是本申请中提出的研究的目标。在第一个具体目标中，我们将讨论EPO的局部递送而不是全身递送是否能够使我们进一步增强恢复，从而为开发创新的局部递送方法以增强/诱导修复奠定基础。EPO的多效性多器官效应，加上局部创伤性损伤的局部治疗的外科和医学焦点，支持这种有效的药理学生物调节剂的局部应用。这实际上将EPO的作用直接集中在损伤部位，消除了继发性作用，并能够以临床相关和靶向的方式优化治疗。在 在第二个具体目标中，我们将检验这样的假设，即EPO的作用机制至少有一部分来自于对雪旺细胞的有益作用，雪旺细胞通过使穿过这些神经的轴突髓鞘化来支持外周神经的功能。总的来说，EPO作用的靶细胞的鉴定将使我们能够更好地确定益处如何发生。在这一特定目标中，我们还将开始梳理支持EPO影响的潜在信号，为设想专注于操纵EPO受体途径中关键信号参与者的辅助治疗提供基础。上述具体目标将代表拟议计划的研究培训部分，以支持临床医生/外科医生John Elfar MD的过渡，他正在将其学术角色扩展到临床医生科学家轨道。拟议的研究培训计划定位于一个强大的指导和教学培训计划的背景下，共同代表了一个多方面的培训环境，旨在确保埃尔法尔博士成功的职业过渡。

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.