Phrenic Afferents and Neuromuscular Plasticity Following Spinal Cord Injury

项目摘要/摘要 候选人：斯特里特博士的职业目标是通过翻译的、基础的 科学通过建立一个以呼吸控制机制为重点的独立研究计划，以及 开发治疗策略来治疗发生在神经肌肉期间的肺功能不全 减损。研究和职业发展计划经过精心设计，以提供 Streeter博士建立一条新的、独立的研究路线所需的技能，包括以下内容 目标：1)获得呼吸神经生物学和心血管控制方面的核心知识，2)进一步获得 研究方法、技术和科学写作方面的专业知识，以及3)培养学术领导力 技能。环境：富勒博士和达文波特博士是杰出的导师，有成功的记录 指导者。富勒博士在脊髓损伤(SCI)和神经可塑性方面拥有专业知识，达文波特博士是一位 关于膈神经传入和呼吸控制的权威。两家公司都有NIH的资金和生产性实验室，以及 将提供资源来帮助候选人完成她的研究项目。赞助机构，即 佛罗里达大学是进行导师研究的理想场所，因为有优秀的教师导师，顶尖的- 呼吸研究和康复中心内的缺口设施和机会。研究： 这项拟议的研究将确定膈神经传入对完整脊柱的呼吸控制的贡献。 和受伤的啮齿动物。颈部脊髓损伤破坏了对主要吸气肌、横隔肌的下行驱动， 并导致严重的呼吸障碍。横隔膜(膈)感觉神经元是一种新的 由于它们在调节呼吸活动方面的作用，因此成为目标。这项建议的根本目标是 确定颈脊髓损伤后膈神经传入对呼吸运动输出的功能贡献。 在亚急性(3-4周)颈椎脊髓损伤的大鼠中，提出了三个特定的目标：目标1：检验假设 急性激活膈神经传入可增加膈神经运动输出；目的2：验证以下假设 重复激活膈神经传入诱发与功能改变相关的膈运动可塑性 脊髓的连通性；目的3：检验以下假设：在 临床使用的隔膜起搏策略，改善了呼吸神经肌肉控制。由于个人 患有颈椎脊髓损伤的患者也是发生令人憎恶的心血管反应的最高风险(例如， 自主神经反射障碍)和激活膈神经传入可能是心率和动脉的强大调节器 血压，我们将在每个目标中评估这些变量。增加对心血管疾病的关注 法规为斯特里特博士提供了额外的职业发展机会，我们聘请了一位 这一领域(海沃德博士)在指导团队中服务。我们建议使用已建立的啮齿动物模型 颈椎SCI(C2半切)和包括在体神经生理学、电学在内的多学科方法 刺激、多电极记录、免疫组织化学和慢性肌电记录/刺激。

PROJECT SUMMARY/ABSTRACT CANDIDATE: Dr. Streeter’s career objective is to improve human medicine through translational, basic science by establishing an independent research program focused on mechanisms of respiratory control, and developing therapeutic strategies to treat pulmonary insufficiencies that occur during neuromuscular impairments. The research and career development plans have been carefully designed to provide the necessary skills for Dr. Streeter to establish a novel, independent line of research and include the following objectives: 1) acquire core knowledge in respiratory neurobiology and cardiovascular control, 2) gain further expertise in research methodology, techniques, and scientific writing, and 3) develop academic leadership skills. ENVIRONMENT: Drs. Fuller and Davenport are exceptional mentors, with a track record of successful mentees. Dr. Fuller has expertise in spinal cord injury (SCI) and neuroplasticity, and Dr. Davenport is an authority on phrenic afferents and respiratory control. Both have NIH funding and productive laboratories, and will provide the resources to assist the candidate in her research project. The sponsoring institution, the University of Florida, is an ideal place to conduct the mentored studies due to outstanding faculty mentors, top- notch facilities, and opportunities within the Center for Respiratory Research and Rehabilitation. RESEARCH: The proposed research will determine the contribution of phrenic afferents to respiratory control in spinal intact and injured rodents. Cervical SCI disrupts descending drive to the primary inspiratory muscle, the diaphragm, and results in a profound breathing impairment. Diaphragm (phrenic) sensory afferent neurons are a novel target due to their role in the regulation of respiratory activity. The fundamental goal of this proposal is to determine the functional contribution of phrenic afferents to respiratory motor output following cervical SCI. Three specific aims are proposed in rats with sub-acute (3-4 wks) cervical SCI: AIM 1: To test the hypothesis that acute activation of phrenic afferents increases phrenic motor output; AIM 2: To test the hypothesis that repeated activation of phrenic afferents induces phrenic motor plasticity associated with altered functional connectivity in the spinal cord; AIM 3: To test the hypothesis that activation of phrenic afferents during the clinically used strategy of diaphragm pacing, improves respiratory neuromuscular control. Since individuals with cervical SCI are also at the highest risk for developing abhorrent driven cardiovascular responses (e.g., autonomic dysreflexia) and activation of phrenic afferents can be powerful regulator of heart rate and arterial blood pressure, we will evaluate these variables during each aim. The added focus on cardiovascular regulation provides an additional career development opportunity for Dr. Streeter, and we recruited an expert in this area (Dr. Hayward) to serve on the mentoring team. We propose to use an established rodent model of cervical SCI (C2 hemisection) and a multi-disciplinary approach including in vivo neurophysiology, electrical stimulation, multi-electrode recordings, immunohistochemistry and chronic EMG recordings/stimulation.