This project will test the central hypothesis that cellular transplants of Schwann cells genetically modified to produce augmented amounts of neuro-trophins will promote CNS repair. Schwann cells are readily obtainable by peripheral nerve biopsy, sustainable as purified primary cultures, and possess intrinsic properties that favor their use in CNS repair, including the ability to myelinate CNS or PNS axons and the ability to secrete extracellular matrix molecules to support and guide new axonal growth. In extensive preliminary experiments, the investigators have transduced Schwann cells to produce and secrete supraphysiological levels of human nerve growth factor (hNGF) and human neurotrophin-3 (hNT3). In proposed experiments, two in vivo models will be used to evaluate the ability of genetically modified Schwann cells to promote neural repair. A spinal cord injury model will examine the ability of genetically modified Schwann cells to promote axonal regrowth. A model of basal forebrain cholineric neuronal degeneration will examine whether genetically modified Schwann cells rescue degenerating neurons. The choice of neurotrophic factors is based upon published data from the principal investigator's laboratory demonstrating in vivo axonal regeneration and neuronal rescue using neurotrophin infusions or grafts of genetically modified fibroblasts. Preliminary in vivo Schwann cell data indicates the practicality and feasibility of addressing the proposal's central hypothesis in these models. The following Specific Aims will be addressed: 1) Determine whether primary Schwann cells genetically modified to express and secrete augmented amounts of human nerve growth factor (hNGF) will promote axonal repair after spinal cord injury. 2) Determine whether primary Schwann cells genetically modified to express and secrete augmented amounts of human neurotrophin-3 (hNT3) will promote axonal repair after spinal cord injury. 3) Determine whether primary Schwann cells genetically modified to express and secrete augmented amounts of human NGF will rescue degenerating host cholinergic neurons in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037083-03
Application #
6126365
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Chiu, Arlene Y
Project Start
1997-12-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2001-11-30
Support Year
3
Fiscal Year
2000
Total Cost
$195,870
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
Conner, James M; Franks, Kevin M; Titterness, Andrea K et al. (2009) NGF is essential for hippocampal plasticity and learning. J Neurosci 29:10883-9
Blesch, Armin; Tuszynski, Mark H (2002) Spontaneous and neurotrophin-induced axonal plasticity after spinal cord injury. Prog Brain Res 137:415-23
Jones, Leonard L; Yamaguchi, Yu; Stallcup, William B et al. (2002) NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. J Neurosci 22:2792-803
Lacroix, Steve; Chang, Leon; Rose-John, Stefan et al. (2002) Delivery of hyper-interleukin-6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth. J Comp Neurol 454:213-28
Blesch, Armin; Lu, Paul; Tuszynski, Mark H (2002) Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Res Bull 57:833-8
Blesch, A; Tuszynski, M H (2001) GDNF gene delivery to injured adult CNS motor neurons promotes axonal growth, expression of the trophic neuropeptide CGRP, and cellular protection. J Comp Neurol 436:399-410
Weidner, N; Ner, A; Salimi, N et al. (2001) Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc Natl Acad Sci U S A 98:3513-8
Blesch, A; Conner, J M; Tuszynski, M H (2001) Modulation of neuronal survival and axonal growth in vivo by tetracycline-regulated neurotrophin expression. Gene Ther 8:954-60
Jones, L L; Tuszynski, M H (2001) Chronic intrathecal infusions after spinal cord injury cause scarring and compression. Microsc Res Tech 54:317-24
Lu, P; Blesch, A; Tuszynski, M H (2001) Neurotrophism without neurotropism: BDNF promotes survival but not growth of lesioned corticospinal neurons. J Comp Neurol 436:456-70

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