Small Molecule Induced Astrogliogenesis

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DESCRIPTION (provided by applicant): Injury and/or dysfunction of astroglia appears to be a component of numerous neurological disorders. Replacement of these cells might be a novel and potent therapy- but engraftment approaches are therapeutically challenging. Adult NG2 cells- the resident adult brain progenitors for oligodendroglia and astroglia are abundant in the rodent and human CNS. We propose to screen rodent and human NG2 cells with a chemical/drug library (singly and in matrix combination) to identify small molecules capable of differentiating these cells to astroglia in vitro and in vivo. We have generated appropriate reporter cells and animals for these assays including rodent NG2-dsRed/GLT1-eGFP, NG2-dsRed-/GLT1 luciferase and human glial progenitor/EAAT2 luciferase cell lines-all suitable for identifying molecules that differentiate progenitors into astroglia. We also have generated the necessary mouse models including NG2/GLT1 BAC reporter mice to evaluate the in vivo efficacy of new astrocyte generation. For future studies, we will test active compounds in our rodent models of neurodegeneration (e.g. G93A SOD1 mouse) to determine the efficacy of the agents in generating new astroglial in diseased mouse models. The aims of the study include: Aim1) Generation and validation of NG2-progenitor/astroglial reporter cell lines for use in drug discovery assays, including rodent NG2 reporter cell lines from NG2-astroglia reporter mice and human progenitor-reporter cell lines. Aim 2) Identification of astroglial transforming small molecules from a diverse chemical compound library and a library of FDA approved drugs in rodent reporter cells, followed by functional validation of new astrogliogenesis from these gliogenic drugs. Finally, the new gliogenic drugs will be validated in the human progenitor cell lines including cell-specific markers and functional activity in vitro. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: This proposal is solely focused on the use of relevant rodent and human progenitor cells as a discovery tool to identify drugs would could transdifferentiate -in vivo-existing adult glial progenitor cells and lead to the generation of new glial cells. The generation of new astroglial cells could be therapeutically valuable for neurological diseases including ALS, Huntington's disease, Alzheimer's disease ,epilepsy, multiple sclerosis and transverse myelitis. Most importantly, it could generate adult stem cell therapy- by activating endogenous adult CNS progenitor cells to differentiate into new astroglia-thereby eliminating need for external cellular based therapy. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page