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

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 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.