Erythropoietin for Neuroregeneration

促红细胞生成素促进神经再生

• 批准号: 8441814
• 负责人: John Elfar
• 金额: $ 8.49万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441814
• 关键词: Acute; Address; Adjuvant Therapy; Adverse effects; Axon; Bolus Infusion; Brachial plexus structure; Cells; Chronic; Clinical; Clinical Research; Coculture Techniques; Coupled; Crush Injury; Data; Development; Dose; Ensure; Environment; Erythropoietin; Erythropoietin Receptor; FDA approved; Fibrin Tissue Adhesive; Foundations; Fracture; Goals; Harvest; In Vitro; Individual; Injury; Innovative Therapy; Intervention; Laceration; Mediating; Medical; Medical center; Mentors; Methods; Mus; Myelin; Nerve; Nerve Tissue; Nerve compression syndrome; Neurons; Operative Surgical Procedures; Organ; Orthopedic Surgery procedures; Orthopedics; Outcome; Pathway interactions; Patients; Peripheral Nerves; Peripheral nerve injury; Positioning Attribute; Public Health; Recovery; Recovery of Function; Research; Research Training; Role; Running; Schwann Cells; Scientist; Signal Pathway; Signal Transduction; Site; Speed; Spinal Ganglia; Staging; Supporting Cell; Surgeon; System; Testing; Therapeutic Agents; Therapeutic Effect; Time; Tissues; Training; Training Programs; Translations; Trauma; Traumatic Brain Injury; Universities; Walking; axon regeneration; base; career; clinically relevant; design; dosage; efficacy testing; functional outcomes; functional restoration; improved; in vivo; injured; innovation; interest; myelination; neuroprotection; novel; outcome forecast; programs; public health relevance; receptor expression; remyelination; repaired; research study; response; sciatic nerve; trauma centers

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.

描述（由申请人提供）：周围神经损伤是一个重大的公共卫生问题，常见于一级创伤中心收治的患者以及多达 30% 的脑外伤患者中。该领域干预的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，我们最近发现全身促红细胞生成素 (EPO) 给药可加速坐骨神经实验性挤压损伤后的功能恢复，即使是在损伤后一周给予 EPO。这些发现已经导致海外启动临床研究。了解 EPO 如何诱导这种有益作用将使我们能够设计可优化其治疗效果的条件和剂量策略；这是本申请中提出的研究的目标。在第一个具体目标中，我们将解决以下问题：EPO 的局部递送（而不是全身递送）是否将使我们能够进一步增强恢复，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局部治疗的外科和医学重点，支持这种有效的药理生物调节剂的局部应用。实际上，这将 EPO 的作用直接集中在损伤部位，消除了副作用，并能够以临床相关和有针对性的方式优化治疗。在 第二个具体目标，我们将检验以下假设：EPO 作用机制的至少一部分源自对施万细胞的有益作用，施万细胞通过使穿过这些神经的轴突有髓鞘来支持周围神经的功能。总体而言，识别 EPO 作用的靶细胞将使我们能够更好地确定益处是如何发生的。在这个具体目标中，我们还将开始梳理支持 EPO 影响的潜在信号传导，为设想专注于操纵 EPO 受体途径中关键信号传导参与者的辅助疗法提供基础。上述具体目标将代表拟议计划的研究培训部分，以支持 John Elfar 博士（医学博士）的过渡，他是一名临床医生/外科医生，正在将其学术角色扩展到临床科学家轨道。拟议的研究培训计划以强有力的指导和教学培训计划为背景，该计划共同代表了一个多方面的培训环境，旨在确保 Elfar 博士成功的职业转型。