Most neurons of the adult central nervous system are terminally differentiated, exist through the life of the organism and, when they die, are not replaced. However, evidence exists that small populations of neurons continue to be born in the adult ventricular zone and hippocampus. Given adult hippocampal granule cells continue to be born through the life of the rodent and FGF-2 can induce hippocampal neuroblast proliferation in vitro , we designed a set of experiments to determine if adult hippocampal cells could be isolated and expanded in vitro to an adequate number for transplantation back into the adult hippocampus. Our results show that cells of the adult nervous system can be isolated and characterized, expanded indefinitely in vitro , genetically labeled in vitro , and transplanted back into the adult central nervous system where they can survive and differentiate in a target-specific manner into neurons. In this grant we plan to extend these observations by conducting the following experiments. 1) We will isolate individual cells of the expanded population of the progenitor cells and grow them as clones to determine the pluripotentiality of the progeny of each of the clones. We will define conditions that influence the fate of the progenitor cells toward glial or neuronal lineage. 2) We will determine if, and to what extent, adult progenitors survive engraftment to the developing and adult brain. We will then determine whether the grafted cells will differentiate and which phenotypic markers they express at different time points following implantation. Finally in this aim we will determine exogenous and endogenous factors that influence the extent of cell survival and the fate of cells following grafting. 3) We will implant the cells into the damaged CNS to determine if they can participate in the repair process, or replace missing cells. Independently of our success in the preceding component of this aim we will genetically engineer the progenitor cells to make and secrete the product, then implant the cells into a relevant animal model. Finally in this aim we will inject FGF-2 chronically in the adult brain to induce proliferation and differentiation of the endogenous progenitor cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006088-14
Application #
6163763
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Wise, Bradley C
Project Start
1985-07-01
Project End
2002-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
14
Fiscal Year
2000
Total Cost
$393,923
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jessberger, Sebastian; Gage, Fred H (2008) Stem-cell-associated structural and functional plasticity in the aging hippocampus. Psychol Aging 23:684-91
Lein, Edward S; Callaway, Edward M; Albright, Thomas D et al. (2005) Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J Comp Neurol 485:1-10
Pizzo, Donald P; Paban, Veronique; Coufal, Nicole G et al. (2004) Long-term production of choline acetyltransferase in the CNS after transplantation of fibroblasts modified with a regulatable vector. Brain Res Mol Brain Res 126:1-13
Markakis, Eleni A; Palmer, Theo D; Randolph-Moore, Lynne et al. (2004) Novel neuronal phenotypes from neural progenitor cells. J Neurosci 24:2886-97
Lein, Ed S; Zhao, Xinyu; Gage, Fred H (2004) Defining a molecular atlas of the hippocampus using DNA microarrays and high-throughput in situ hybridization. J Neurosci 24:3879-89
Klassen, Henry; Imfeld, Karen L; Ray, Jasodhara et al. (2003) The immunological properties of adult hippocampal progenitor cells. Vision Res 43:947-56
Rhodes, Justin S; van Praag, Henriette; Jeffrey, Susan et al. (2003) Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behav Neurosci 117:1006-16
Vallieres, Luc; Campbell, Iain L; Gage, Fred H et al. (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22:486-92
Zhao, X; Lein, E S; He, A et al. (2001) Transcriptional profiling reveals strict boundaries between hippocampal subregions. J Comp Neurol 441:187-96
Palmer, T D; Willhoite, A R; Gage, F H (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479-94

Showing the most recent 10 out of 71 publications