Coupling spinal gene therapy with intermittent hypoxia to improve breathing after spinal cord injury

 描述(由申请人提供)：这项博士后培训计划有两个主要目标。首先，拟议的工作和培训计划将为一位有前途的青年科学家提供学术研究方面的培训，并将为她提供职业发展机会，以促进她成为一名独立科学家。其次，总体的科学目标是测试一种新的方法来改善颈髓损伤(SCI)后的呼吸运动功能--这是一个威胁生命的问题，治疗选择有限，而且无法治愈。建议的研究集中于结合两种新的方法来改善高度颈椎SCI后的呼吸恢复：使用基于AAV的基因治疗过表达脊髓BDNF和间歇性低氧。这项拟议工作的一个非常独特的特点是使用多电极阵列来记录单个脊髓中间神经元。作为一个领域，我们几乎对CSCI后脊髓固有网络--可能是脊髓损伤康复的关键部分--如何改变一无所知。此外，包括间歇性低氧和基因治疗在内的许多治疗策略正在取得进展，但对这些治疗方法调节固有脊髓网络活动的机制尚不清楚。明确慢性CSCI后的脊髓回路对于设计循证呼吸康复和脊髓修复方法至关重要。这一建议的两个具体目的是：1)检验脊髓BDNF受控过表达调节颈脊髓间神经元活性以增强CSCI后网络的兴奋性并促进其恢复的假说；2)检验CSCI后脊髓BDNF过表达与IH协同作用改变颈脊髓间神经元的兴奋性并增强呼吸神经可塑性的疗效的假说。为了验证我们的假设，我们将使用已建立的CSCI啮齿动物模型(C2半切；C2Hx)和多学科方法，包括体内神经生理学、基于AAV的技术、多电极阵列、组织学和行为结果测量。如果成功，这项拟议的研究将在治疗颈髓损伤后呼吸功能障碍的方法方面取得革命性进展。

 DESCRIPTION (provided by applicant): There are two overarching objectives of this postdoctoral training proposal. First, the proposed work and training plan will provide a promising young scientist with training in academic research and will provide career development opportunities to facilitate her achievement of becoming an independent scientist. Second, the overall scientific aim is to test a novel approach for improving respiratory motor function after cervical spinal cord injury (SCI) - a life-threatening problem with limited treatmen options and no cure. The proposed studies focus on coupling two novel methods to improve respiratory recovery following a high cervical SCI: overexpression of spinal BDNF using AAV-based gene therapy and intermittent hypoxia. A highly unique feature of the proposed work is the use of a multi-electrode array to record individual spinal interneurons. As a field, we know almost nothing about how the propriospinal network - likely a key part of SCI rehabilitation - is altered following cSCI. Additionally, many therapeutic strategies including intermittent hypoxia and gene therapy are progressing without a clear understanding of the mechanisms by which these therapies modulate the activity of the propriospinal network. Defining the spinal circuitry after chronic cSCI is essential for designing evidence-based respiratory rehabilitation and spinal cord repair approaches. The two specific aims of this proposal are: 1) To test the hypothesis that controlled overexpression of spinal BDNF modulates the activity of cervical spinal interneurons to enhance the excitability of the network and promote recovery following cSCI.; and 2) To test the hypothesis that following cSCI, overexpression of spinal BDNF coupled with IH act synergistically to alter the excitability of cervical spinal interneurons and enhance the efficacy of respiratory neuroplasticity. To test our hypotheses, we will use an established rodent model of cSCI (C2 hemisection; C2Hx) and a multi-disciplinary approach including in vivo neurophysiology, AAV-based technology, multi-electrode arrays, histology, and behavioral outcome measures. If successful, the proposed research will make transformative advances in the approach to treating respiratory dysfunction after cervical spinal cord injury.