Bone marrow-derived stem cells incorporate into multiple tissue types in adult mammals, where they give rise to cells of multiple lineages that cross classic embryological trilaminar boundaries [9,11,17,21,31,40,41]. This recent discovery has opened the possibility that bone marrow transplantation could be clinically useful to treat a broad spectrum of pathologies. Recently, marrow-derived progenitor cells have been shown to migrate and incorporate into the brain to give rise to cells of neuroectodermal lineage, (astrocytes and neurons), in addition to microglia [4,7,25]. Importantly, marrow-derived progenitors appear to display preferential homing to regions of CNS gliosis and degeneration [8], consistent with studies in peripheral tissues demonstrating enhanced engraftment of multi-potential marrow-derived stem cells into sites of injury [21,31] [Jackson, 2001 #360]. The focus of the current proposal is to explore the migration and differentiation of marrow-derived stem cells into the brain in a rodent model of Parkinson's disease, the MPTP-treated mouse. Questions to be addressed in this proposal include: Do marrow-derived progenitors display selective homing to the damaged nigra and striatum in response to MPTP-induced degeneration? If so, do they give rise to cells of neuroectodermal lineage? What is their contribution to the gliosis that accompanies nigrostriatal degeneration? To track marrow-derived progenitors within the CNS, we will utilize bone marrow from transgenic mice that express an enhanced green fluorescent protein (GFP) under the beta-actin promoter. The migration and differentiation of marrow-derived progenitors will be studied in chimeric mice whose endogenous hematopoietic systems have been completely reconstituted with GFP-expressing cells prior to MPTP- treatment, and in mice that receive acute intravascular injections of GFP+ expressing cells prior to MPTP-treatment, and in mice that receive acute intravascular injections of GFP+ expressing marrow following the onset of MPTP-induced degeneration. The immediate goal of the proposed studies is to delineate the relationship between marrow-derived progenitors and the brain in a rodent model of Parkinson's disease. If successful, these studies may provide the basis for future work to development new non-invasive gene therapies for Parkinson's disease, using accessible, renewable and autologous bone marrow stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS043646-01
Application #
6479831
Study Section
Special Emphasis Panel (ZNS1-SRB-K (05))
Program Officer
Sheehy, Paul A
Project Start
2002-02-15
Project End
2004-01-31
Budget Start
2002-02-15
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$187,500
Indirect Cost
Name
University of New Mexico
Department
Neurosciences
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Kokovay, Erzsebet; Li, Lu; Cunningham, Lee A (2006) Angiogenic recruitment of pericytes from bone marrow after stroke. J Cereb Blood Flow Metab 26:545-55
Kokovay, Erzsebet; Cunningham, Lee Anna (2005) Bone marrow-derived microglia contribute to the neuroinflammatory response and express iNOS in the MPTP mouse model of Parkinson's disease. Neurobiol Dis 19:471-8