In both tuberous sclerosis (TSC) and neurofibromatosis type 2 (NF2) loss of gene function alters thedevelopment of the nervous system, resulting in abnormal structures and benign tumors. In the case of TSC,the target cells are thought to be neuroprecursor cells (NPCs), astrocytes and young neurons, and in thecase of NF2, Schwann cells in peripheral nerves, as well as arachnoidal cells in the brain. Adeno-associatedvirus (AAV) will be used to elucidate cells of origin and create mouse models of brain lesions in TSC andschwannomas in NF2; both AAV and herpes simplex virus (HSV) amplicon vectors will be used to exploretreatment paradigms for these lesions.
Aim 1 a is directed towards determining the contribution of NPCs tobrain lesions in a mouse model of TSC. Mice homozygous for both conditional, Tsc1 knock-out and lacZknock-on alleles will receive intracranial ventricular (ICV) injections of AAV vectors bearing Cre recombinaseunder NPC and constitutive promoters at different times in brain development. The fate of Tsc1 null/lacZ+cells will be evaluated to determine their contribution to enlarged neurons, multi-lineage phenotypes, andproliferative foci in the brain.
In Aim 1 b we will evaluate the ability of AAV vectors encoding hamartin tocorrect the neurologic phenotype of Tsct dc x synapsin-1-Cre offspring following injection into the developingbrain as compared to rapamycin treatment. Mice will be monitored for neuroanatomical features, as well asweight gain, seizures and age of death.
Aim 2 is directed towards identifying disregulated microRNAs inhuman meningioma tumors relative to merlin status and to normal cells of origin. Correlations will be madewith clinical status, neuropathology, genomic changes and mRNA levels. Validated microRNA and mRNAchanges will be evaluated for effects on growth of meningioma cells and tumors.
Aim 3 is designed todevelop a model for spontaneous Nf2-null schwannomas using conditional Nf2 knock-out mice and AAV Crevectors in a nerve injury model, including evaluation of role of p53 status and monitoring by bioluminescenceimaging. In addition we will evaluate the ability of HSV amplicon vectors expressing an apoptotic protein toachieve regression of implanted (and spontaneous) human schwannoma tumors. These studies will informtherapeutic strategies in two ways: first, by elucidating the specific neural cell types, conditions and time atwhich different types of lesions form in the Tsc1-null and NF2-null cells in the nervous system, and second,by evaluating the ability of gene replacement to rescue Tsc1-null neurons and extend lifespan, and to'debulk' schwannoma tumors while sparing neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS024279-20A2
Application #
7454805
Study Section
Special Emphasis Panel (ZNS1-SRB-G (08))
Project Start
Project End
Budget Start
2008-05-15
Budget End
2009-04-30
Support Year
20
Fiscal Year
2008
Total Cost
$291,359
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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