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

 描述（由申请人提供）：这个博士后培训计划有两个总体目标。首先，拟议的工作和培训计划将为一名有前途的年轻科学家提供学术研究方面的培训，并将提供职业发展机会，以促进她成为一名独立的科学家。第二，总体科学目标是测试一种改善颈脊髓损伤（SCI）后呼吸运动功能的新方法-这是一种治疗选择有限且无法治愈的危及生命的问题。拟议的研究集中在耦合两种新的方法，以改善呼吸恢复后，高颈脊髓损伤：过度表达的脊髓BDNF使用基于AAV的基因治疗和间歇性缺氧。所提出的工作的一个非常独特的功能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，我们几乎不知道脊髓本体网络-可能是脊髓损伤康复的关键部分-在脊髓损伤后是如何改变的。此外，许多治疗策略，包括间歇性缺氧和基因治疗正在取得进展，而这些疗法调节的propriospinal网络的活动的机制没有明确的理解。定义慢性脊髓损伤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。本研究的两个具体目的是：1）验证脊髓BDNF的受控过表达调节颈脊髓中间神经元的活性以增强网络的兴奋性并促进cSCI后的恢复的假设; 2）验证cSCI后脊髓BDNF过表达与IH协同作用改变颈髓中间神经元的兴奋性并增强呼吸神经可塑性的假设。为了验证我们的假设，我们将使用一个已建立的啮齿动物模型cSCI（C2半切; C2 Hx）和多学科的方法，包括在体内神经生理学，基于AAV的技术，多电极阵列，组织学和行为结果的措施。如果成功，拟议的研究将在治疗颈脊髓损伤后呼吸功能障碍的方法方面取得变革性进展。

 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.