Erythropoietin for Neuroregeneration

描述(申请人提供)：周围神经损伤是一个主要的公共卫生问题，经常见于I级创伤中心的患者和多达30%的创伤性脑损伤患者。在这一领域进行干预的一个主要目标是加速康复，以便尽快恢复功能。然而，实现这一目标的进展有限。有趣的是，我们最近发现，在实验性坐骨神经挤压伤后，即使在损伤后一周给予EPO，全身促红细胞生成素(EPO)也能加速功能恢复。这些发现已经导致了海外临床研究的启动。了解EPO如何产生这种有益效果将使我们能够设计条件和剂量策略，以优化其治疗效果；这是本申请中提出的这项研究的目标。在第一个具体目标中，我们将解决这样一个问题，即本地交付EPO而不是系统交付是否使我们能够进一步促进恢复，从而为发展创新的本地交付方法奠定基础，以加强/诱导修复。促红细胞生成素的多器官效应，再加上外科和医学对局部创伤局部治疗的关注，证明了这种有效的药理生物调节剂的局部应用。这实际上将促红细胞生成素的作用直接集中在损伤部位，消除了继发性影响，并使临床相关和有针对性的治疗得以优化。在……里面 第二个具体目标是，我们将检验这一假设，即EPO的作用机制至少有一部分来自对雪旺细胞的有益影响，雪旺细胞是通过对贯穿周围神经的轴突进行髓鞘处理来支持周围神经功能的细胞。总体而言，确定EPO作用的目标细胞(S)将使我们能够更好地确定效益是如何发生的。在这个特定的目标中，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受体途径中的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/外科医生约翰·埃尔法尔博士的过渡，他正在将自己的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是在一个强大的指导和说教培训计划的背景下提出的，这些计划共同代表了一个旨在确保埃尔法博士成功过渡职业生涯的多方面培训环境。

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.