Delivery of neurotrophic factors to sites of spinal cord injury (SCI) has been shown to induce axonal growth from different neuronal populations. While cellular growth factor gene delivery is a potent means of promoting the growth of several axonal populations into spinal cord lesion sites, novel strategies need to be developed to increase the distance of axonal growth and to define the conditions needed to direct axonal growth across a lesion site. In studies supported by an R21 grant we have determined that in vivo neurotrophin gene transfer beyond a spinal cord lesion site establishes gradients of neurotrophic factors and can thereby direct axons across a spinal cord lesion site. The mechanisms underlying morphological and functional outcomes and the conditions needed to achieve persistent morphological and functional improvements will be studied in this proposal. We will investigate the hypothesis that transient, regulated gradients of the neurotrophin BDNF will be sufficient to induce axonal bridging across a spinal cord lesion site, morphological plasticity and reinnervation, resulting in persistent functional recovery. BDNF gradients across a cervical spinal cord lesion site filled with bone marrow stromal cells will be established using in vivo lentiviral gene transfer. Mechanisms of morphological and functional outcomes will be investigated in detail in well-defined transection models of SCI that allow the discrimination between sprouting of spared projections and true regeneration of injured axons. Anterograde and retrograde tracing and specific re-transections will allow the identification of different mechanisms that could contribute to reinnervation and functional recovery. Using tetracycline-regulated, lentiviral BDNF gene transfer we will define the conditions needed to retain the connectivity and function of regenerated axons and we will determine whether a practical need for extended gene expression exists for the formation and maintenance of newly formed synapses. If successful, these studies will establish practical strategies for growth factor delivery to the injured spinal cord that can lead to the development of novel therapies for spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS054883-03S2
Application #
7869547
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2007-04-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$58,393
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Hou, Shaoping; Blesch, Armin; Lu, Paul (2014) A radio-telemetric system to monitor cardiovascular function in rats with spinal cord transection and embryonic neural stem cell grafts. J Vis Exp :e51914
Hou, Shaoping; Tom, Veronica J; Graham, Lori et al. (2013) Partial restoration of cardiovascular function by embryonic neural stem cell grafts after complete spinal cord transection. J Neurosci 33:17138-49
Hou, Shaoping; Lu, Paul; Blesch, Armin (2013) Characterization of supraspinal vasomotor pathways and autonomic dysreflexia after spinal cord injury in F344 rats. Auton Neurosci 176:54-63
Blesch, Armin; Fischer, Itzhak; Tuszynski, Mark H (2012) Gene therapy, neurotrophic factors and spinal cord regeneration. Handb Clin Neurol 109:563-74
McCall, Julianne; Nicholson, Lashae; Weidner, Norbert et al. (2012) Optimization of adult sensory neuron electroporation to study mechanisms of neurite growth. Front Mol Neurosci 5:11
Blesch, Armin; Lu, Paul; Tsukada, Shingo et al. (2012) Conditioning lesions before or after spinal cord injury recruit broad genetic mechanisms that sustain axonal regeneration: superiority to camp-mediated effects. Exp Neurol 235:162-73
Franz, Steffen; Weidner, Norbert; Blesch, Armin (2012) Gene therapy approaches to enhancing plasticity and regeneration after spinal cord injury. Exp Neurol 235:62-9
Hou, Shaoping; Nicholson, LaShae; van Niekerk, Erna et al. (2012) Dependence of regenerated sensory axons on continuous neurotrophin-3 delivery. J Neurosci 32:13206-20
McCall, Julianne; Weidner, Norbert; Blesch, Armin (2012) Neurotrophic factors in combinatorial approaches for spinal cord regeneration. Cell Tissue Res 349:27-37
Brock, John H; Rosenzweig, Ephron S; Blesch, Armin et al. (2010) Local and remote growth factor effects after primate spinal cord injury. J Neurosci 30:9728-37

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