Grant funds are requested to support a new research Program Project aimed at initiating an exploration of the potential of embryonic stem (ES) cell transplantation for restoring lost functions after spinal cord injury. Members of the proposed Project team have already developed experience working with mouse ES cells differentiated down neural lineages, methods for reducing cell death in the nervous system, and rodent models of traumatic spinal cord injury. In the experiments that form the specific background for the present proposal, Project team members have obtained evidence that mouse ES-cell derived neural lineage cells (ESNLCs) can be successfully transplanted into the syrinx/cyst that forms nine days after impact injury to the rat spinal cord . These transplanted ESNLCs survived for at least many weeks, partially filling the syrinx and migrating into host tissue, and expressed markers for differentiated oligodendrocytes, astrocytes, and neurons. The requested Program Project funding would enable Project team members to build on these early experiments in a systematic and hypothesis-driven fashion. Based on direct observations that a majority of transplanted ESNLCs die over the first 48 hours following transplantation and that neurons in particular continue to die over subsequent days, the emphasis of the experiments proposed here will be on improving the survival of transplanted ESNLCs through pharmacological and genetic engineering approaches aimed at blocking apoptosis and excitotoxicity. It is anticipated that work performed in subsequent years may be directed at optimizing the ESNLC transplantation procedure in other ways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS039577-04
Application #
6625482
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Chiu, Arlene Y
Project Start
1999-12-17
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
4
Fiscal Year
2003
Total Cost
$1,067,714
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Vadivelu, Sudhakar; Stewart, Todd J; Qu, Yun et al. (2015) NG2+ progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury. Stem Cells Transl Med 4:401-11
Becker, Daniel; Gary, Devin S; Rosenzweig, Ephron S et al. (2010) Functional electrical stimulation helps replenish progenitor cells in the injured spinal cord of adult rats. Exp Neurol 222:211-8
Cui, Lin; Jiang, Jun; Wei, Ling et al. (2008) Transplantation of embryonic stem cells improves nerve repair and functional recovery after severe sciatic nerve axotomy in rats. Stem Cells 26:1356-65
Dilmanian, F Avraham; Qu, Yun; Feinendegen, Ludwig E et al. (2007) Tissue-sparing effect of x-ray microplanar beams particularly in the CNS: is a bystander effect involved? Exp Hematol 35:69-77
Huettner, James E; Lu, Aiwu; Qu, Yun et al. (2006) Gap junctions and connexon hemichannels in human embryonic stem cells. Stem Cells 24:1654-67
Vadivelu, Sudhakar; Platik, Marina M; Choi, Luke et al. (2005) Multi-germ layer lineage central nervous system repair: nerve and vascular cell generation by embryonic stem cells transplanted in the injured brain. J Neurosurg 103:124-35
Vadivelu, Sudhakar; Becker, Daniel; McDonald, John W (2005) Generating chimeric spinal cord: a novel model for transplantable oligodendrocyte progenitors derived from embryonic stem cells. Neurosurg Focus 19:E3
Wei, Ling; Cui, Lin; Snider, B Joy et al. (2005) Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia. Neurobiol Dis 19:183-93
Xian, Hai-Qing; Werth, Kelly; Gottlieb, David I (2005) Promoter analysis in ES cell-derived neural cells. Biochem Biophys Res Commun 327:155-62
Lee, Chul-Sang; Tee, Lee Y; Dusenbery, Susan et al. (2005) Neurotrophin and GDNF family ligands promote survival and alter excitotoxic vulnerability of neurons derived from murine embryonic stem cells. Exp Neurol 191:65-76

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