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2002
Fellow
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Alysson Renato Muotri,
Ph.D.
Lab. of: Fred H. Gage, Ph.D.
Laboratory of Genetics
Salk Institute for Biological Studies
10010 North Torrey Pines Road
La Jolla, CA 92037
Tel: (858) 453-4100 x 1004
Fax: (858) 597-0824
Email: muotri@salk.edu
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Country:
BRAZIL
Field:
Neurobiology
Research Interest:
GENETIC ANALYSIS OF NEURAL PROGENITOR
CELLS DIFFERENTIATION IN THE NEURODEGENERATIVE DISEASE ATAXIA TELANGIECTASIA
Neural stem cells (NSCs) are immature, uncommitted cells that exist in
the developing and adult nervous system and are responsible for giving
rise to the vast array of more specialized neural cells of the Central
Nervous System (CNS). Ataxia telangiectasia (A-T) is a genetic disorder
with progressive neurodegeneration caused by mutations in the ATM (ataxia
telangiectasia mutated gene). Dysfunctions arising from a lack of properly
ATM expression during development could potentially manifest themselves
in postmitotic neurons and other nervous system cell types as a decrease
in the ability of the cells to survive, differentiate, or function normally
within the developed CNS. The primary aim of this proposal is to analyze
the development of A-T progenitor cells before and after differentiation
using an ATM gene expression inducible system. The proposed work is to
introduce the ATM cDNA under the control of the tetracycline responsive
element (TRE) in NSC by a virus-based system. To accomplish this goal,
NSCs from Atm -/- mice hippocampus will be infected and neurospheres stimulate
to differentiate in other CNS cells, like neurons, oligodendrocytes and
astrocytes. Adult hippocampus cells will be first targeted because its
ability to generate neural progenitor cells at a significant rate and
to differentiate into all CNS cell types. During the process of differentiation,
the ATM gene expression will be turned on by the addition of tetracycline
in the culture medium. Cells in these different conditions will be analyzed
using microarrays derived from a representational difference analysis
(RDA) subtraction, followed by single-cell RT-PCR, laser capture microdissection
(LCM) and Northern-blot confirmation. When properly applied, this technique
can eliminate the problems of tissue and cellular heterogeneity and this
is likely to provide important insight into A-T and other neurodegenerative
diseases.
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