PDF file: EURASNET Annual Report 2008

alternative splicing, using theEDI minigene reporter. If so,experiments will be initiated todetermine whether the effect isvia a gene silencing mechanisminvolving histone modifications.(month 42)218 Smith and Neugebauer willcollaborate to determine whetherPTB is recruited cotranscriptionallyto target genesidentified in Smith lab bymicroarray analysis (see WP8).PTB-GFP BACs will beestablished (if possible) andstably transfected into cell lines,including mouse C2C12myoblasts. Alternatively, PTBantibodies will employed insplicing factor ChIP. (month 42)219 Bertrand and Neugebauer willcollaborate to determine whethersplicing of HIV nascenttranscripts is co-transcriptional,using a model gene comprising asplit MS2 reporter. ChIP of theMS2 binding protein willindicate when and where alongthe gene splicing catalysisoccurs. (month 42)220 Identification of novel moleculesbased on luciferase modelsubstrates for DMD exon 51skipping and LMNA aberrantsplicing. (month 42)221 Validation of the efficacy ofnovel synthesized compounds inmodel mice for: Mo-MLV, HIV-1, DMD, Breast metastic cancerand HGPS (month 42)222 Validation of modified U7cassetes to correct SMNexpression in a mouse model forSMA (month 42)223 Development of clinically usefuldrugs that direct the splicingpathway: both Antisenseolinucleotides and smallchemical molecules (month 42)224 Schümperli's group will furtherexploit the mouse SMA modelmentioned above to: (i)determine the time point whenSMN production is critical andrequires therapeutic boosting;(ii) study the ability of mutantSMN to counteract the SMAphenotype; (iii) study the role ofSMN in motoneurons; (iv)develop ways to deliver thetherapeutic U7 transgene tomotoneurons. Additionally they13 42 delayed (newdeliverable)Neugebauer13 42 on target Neugebauer14 42 on target Tazi14 42 on target Tazi14 42 on target Tazi14 42 on target Tazi14 42 on target Tazi105