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Abstract
Grant Number: 1R21NS061653-01 Project Title: Cell Based Assays for Compounds That Regulate Tau Exon 10 Splicing
PI Information: Name Title ZHOU, JIANHUA jianhua.zhou@umassmed.edu Abstract: DESCRIPTION (provided by applicant): Tau aggregation is one of the most recognized features in more than 20 neurodegenerative disorders, classified as tauopathies that include Alzheimer's disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and progressive supranuclear palsy (PSP). More than 29 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alter splicing of exon 10, resulting in increase of exon 10 inclusion into the tau mRNA. In several other tauopathies such as PSP and Alzheimer's disease, abnormal splicing with inclusion of exon 10 into more tau mRNA has also been observed. These results indicate that one of the mechanisms that tau accumulates and aggregates in brains of tauopathies is abnormal splicing of the exon 10 towards to a more production of tau with the exon. Therefore, modulation of exon 10 splicing in the tau gene could be potentially targeted for preventing tauopathies. In order to establish a robust cell based system and to identify compounds/drugs that prevent exon 10 inclusion, we studied the mechanisms of tau splicing. We have demonstrated that a minimal distance between exons 10 and 11 is required for correct splicing of exon 10, and our additional preliminary data show that there are distal splicing cis-elements in intron 9. The goal of this proposal is to modify our existing mini reporter genes by including additional cis-elements and to establish a faithful cell based assay for identification of drugs that modulate exon 10 splicing. The assay will be optimized for high throughput screening and pilot screening will be carried out with 1040 FDA approved drugs and compounds.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
drug screening /evaluation, reporter gene, tau protein
combinatorial chemistry, genetic regulatory element
NIH Roadmap Initiative tag, RNA splicing
Institution: UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER, MA 01655 Fiscal Year: 2007 Department: MEDICINE Project Start: 30-SEP-2007 Project End: 31-JAN-2010 ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE IRG: ZMH1