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。在这一领域进行干预的主要目标是加速恢复，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，我们最近发现系统性促红细胞生成素（EPO）可加速实验性坐骨神经挤压损伤后的功能恢复，即使在损伤后一周给予EPO也是如此。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条件和剂量策略，以优化其治疗效果；这是本应用中提出的3个研究的目标。在第一个具体目标中，我们将探讨局部给药而非全身给药是否能进一步促进恢复，从而为开发创新的局部给药方法奠定基础，以加强/诱导修复。EPO的多器官作用，加上局部创伤性损伤的局部治疗的外科和医学重点，证明了这种有效的药理学生物调节剂的局部应用。这实际上是将EPO的作用直接集中在损伤部位，消除了继发性影响，并以临床相关和有针对性的方式优化了治疗。在