Principle Investigator/Program Director (Last, first, middle) Elefant, Felice ABSTRACT: TIP60 and APP in neuronal development Tip60 is a key histone acetyltransferase (HAT) enzyme that plays essential roles in diverse chromatin- mediated biological processes, including gene regulation, apoptosis, cell-cycle regulation, DNA recombination and repair. Tip60 is part of a multi-protein complex that is recruited by transcription factors to the promoters of certain genes where it generally acetylates surrounding histones to activate gene expression. Thus, Tip60 recruitment is involved in epigenetic gene regulation. While it is evident that Tip60 plays a central role in transcriptional control, it remains unclear as to the tissue and cell type-specific developmental pathways and target genes that require Tip60 to function. To investigate the role of TIP60 in multicellular development, our laboratory has identified and cloned the human TIP60 homolog in Drosophila (Dmel TIP60). We have developed a system in transgenic flies that allows for targeted and inducible overexpression of wild-type or dominant negative HAT defective Dmel TIP60 and Dmel TIP60 knockdown in specific tissues, cell types and developmental stages of choice. Using this system, we have determined that Dmel TIP60 is essential for nervous system formation during early development. We show that loss of Dmel TIP60 in the fly brain leads to substantial neuronal loss and lethality. Consistent with our finding, other groups have documented an essential role for Tip60 HAT activity in the transcriptional activation of target genes via amyloid precursor protein (APP) mediated cell signaling pathways proposed to be involved in neuronal development. Intriguingly, TIP60 levels dramatically increase in the brains of young Alzheimer's disease (AD) model mice overproducing APP long before they acquire the A? plaques, neurotoxicity and behavioral abnormalities representative of the disease. These findings provide the basis for our central hypothesis that APP perturbation causes upregulation of endogenous TIP60, leading to misregulation of both TIP60/APP and exclusive TIP60 chromatin-mediated neuronal pathways that is relevant in both development and neurodegeneration. To test this hypothesis, the following specific aims will be carried out.
Aim 1 will identify TIP60 epigenetically regulated target genes that participate in distinct neuronal developmental processes and Aim 2 will determine the extent to which TIP60 chromatin-mediated neuronal processes and target genes are affected by overexpression of APP, in vivo. Such knowledge has important implications for the development of novel chromatin-based therapeutics in TIP60 associated disorders. PHS 398/2590 (Rev. 05/01) Page _____ Continuation Format Page Principle Investigator/Program Director (Last, first, middle) Elefant, Felice NARRATIVE: Our goal of deciphering the role of Tip60 and APP in neuronal development should profoundly enhance our understanding of nervous system development and neurodegenerative disorders. Such knowledge has important implications for the development of novel epigenetic-based therapeutics. PHS 398/2590 (Rev. 05/01) Page _____ Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD057939-05
Application #
8318766
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Oster-Granite, Mary Lou
Project Start
2008-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$242,352
Indirect Cost
$80,784
Name
Drexel University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pirooznia, Sheila K; Elefant, Felice (2013) A HAT for sleep?: epigenetic regulation of sleep by Tip60 in Drosophila. Fly (Austin) 7:99-104
Johnson, Ashley A; Sarthi, Jessica; Pirooznia, Sheila K et al. (2013) Increasing Tip60 HAT levels rescues axonal transport defects and associated behavioral phenotypes in a Drosophila Alzheimer's disease model. J Neurosci 33:7535-47
Lorbeck, Meridith; Pirooznia, Keerthy; Sarthi, Jessica et al. (2011) Microarray analysis uncovers a role for Tip60 in nervous system function and general metabolism. PLoS One 6:e18412
Sarthi, Jessica; Elefant, Felice (2011) dTip60 HAT activity controls synaptic bouton expansion at the Drosophila neuromuscular junction. PLoS One 6:e26202
Lorbeck, Meridith T; Singh, Neetu; Zervos, Ashley et al. (2010) The histone demethylase DmelKdm4A controls genes required for life span and male-specific sex determination in Drosophila. Gene 450:8-17
Singh, Neetu; Lorbeck, Meridith T; Zervos, Ashley et al. (2010) The histone acetyltransferase Elp3 plays in active role in the control of synaptic bouton expansion and sleep in Drosophila. J Neurochem 115:493-504