Phrenic Afferents and Neuromuscular Plasticity Following Spinal Cord Injury

项目总结/摘要 候选人：Streeter博士的职业目标是通过转化，基础和创新来改善人类医学。 科学通过建立一个独立的研究计划，重点是呼吸控制机制， 开发治疗策略以治疗神经肌肉运动期间发生的肺部炎症， 损伤研究和职业发展计划经过精心设计，以提供 斯特里特博士建立一个新的，独立的研究线，包括以下必要的技能 目的：1）获得呼吸神经生物学和心血管控制的核心知识，2）获得进一步的 在研究方法，技术和科学写作方面的专业知识，以及3）发展学术领导力 skills. Fuller和Davenport是杰出的导师，有着成功的业绩记录。 学员Fuller博士在脊髓损伤（SCI）和神经可塑性方面具有专业知识，Davenport博士是一位 膈神经传入和呼吸控制方面的权威。两者都有国家卫生研究院的资金和生产性实验室， 将提供资源，以协助候选人在她的研究项目。主办机构、 佛罗里达大学，是一个理想的地方进行辅导研究，由于优秀的教师导师，顶级- 一流的设施，以及呼吸研究和康复中心内的机会。研究： 这项研究将确定膈神经传入神经在脊髓完整的呼吸控制中的作用。 和受伤的啮齿动物颈椎脊髓损伤破坏了对主要吸气肌，横膈膜的下行驱动， 导致严重的呼吸障碍膈感觉传入神经元是一种新的神经元， 由于它们在呼吸活动调节中的作用，它们是靶点。这项建议的基本目标是 确定颈脊髓损伤后膈神经传入神经对呼吸运动输出的功能贡献。 在亚急性（3-4周）颈脊髓损伤大鼠中提出了三个具体目标：目的1：验证假设 膈神经传入神经的急性激活增加膈神经运动输出;目的2：为了检验这一假设， 重复激活膈传入神经可诱导与功能改变相关的膈运动可塑性 目的3：为了验证这一假设，膈传入神经的激活过程中， 临床上使用的膈肌起搏策略，改善呼吸神经肌肉控制。由于个人 患有颈脊髓损伤的人也处于发展令人厌恶的心血管反应的最高风险（例如， 自主神经反射异常）和膈传入神经的激活可以是心率和动脉血压的有力调节器。 血压，我们将在每个目标期间评估这些变量。增加对心血管疾病的关注 法规为Streeter博士提供了额外的职业发展机会，我们聘请了一位专家， 这一领域（海沃德博士）担任指导小组。我们建议使用已建立的啮齿动物模型， 颈椎SCI（C2半切）和多学科方法，包括体内神经生理学，电 刺激、多电极记录、免疫组织化学和慢性EMG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.