Small RNA mediated regulation of gene expression is a recent addition to fundamental gene regulatory mechanisms that contribute to coordinate temporal and spatial gene expression of possibly every gene of a eukaryotic genome. The predominant sources of small RNA in somatic tissues are miRNA genes that encode short dsRNA hairpins of evolutionary conserved sequences. Disorders of the nervous system, such as schizophrenia, depression, bipolar disorder or autism are poorly understood at a molecular level but presumed to be caused by perturbation in gene regulatory networks of neuronal circuits. In this application we propose to explore if miRNA regulatory networks play a role in these and other diseases of the nervous system. This will be achieved through a highly collaborative and interactive effort of three laboratories that will develop methods for identification of small RNAs and their regulated targets and use biochemical, cell and animal model systems to study the detailed molecular mechanisms of gene regulation.
The specific aims of this study are: 1. Define the small RNA content of anatomical and/or functionally distinct brain regions of normal and disease state. Include in the analysis model neuronal and nervous system cell lines as well as neuronal stem cell progenitors and derived cells or structures. 2. Define the spatial and cell type specific expression of the most abundantly and specifically expressed miRNAs in the brain of mouse, Macaca fascicularis, and human brain (normal and disease states). 3. Define the targets of miRNAs in mouse brain and normal and patient brain regions using genomic and biochemical approaches. 4. Determine the role of miRNAs in neuronal differentiation of mouse embryonic stem cells. Lay statement: Although efforts to identify genes responsible for major depression, bipolar disorder, autism, and schizophrenia have been challenging in the past, the purpose of this study will be to provide an expression atlas of a new class of small non-coding genes (microRNAs) from normal and mentally disabled subjects to determine the role of a subset of the highly expressed microRNAs in the central nervous system. Understanding the specific interactions of microRNAs and the network of genes they target and regulate may ultimately contribute to our understanding and treatment of these debilitating mental illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080442-04
Application #
7798641
Study Section
Special Emphasis Panel (ZMH1-ERB-L (02))
Program Officer
Koester, Susan E
Project Start
2007-07-04
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$572,759
Indirect Cost
Name
Rockefeller University
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Santa-Maria, Ismael; Alaniz, Maria E; Renwick, Neil et al. (2015) Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J Clin Invest 125:681-6
Renwick, Neil; Cekan, Pavol; Bognanni, Claudia et al. (2014) Multiplexed miRNA fluorescence in situ hybridization for formalin-fixed paraffin-embedded tissues. Methods Mol Biol 1211:171-87
Renwick, Neil; Cekan, Pavol; Masry, Paul A et al. (2013) Multicolor microRNA FISH effectively differentiates tumor types. J Clin Invest 123:2694-702
Ascano, Manuel; Gerstberger, Stefanie; Tuschl, Thomas (2013) Multi-disciplinary methods to define RNA-protein interactions and regulatory networks. Curr Opin Genet Dev 23:20-8
Farazi, Thalia A; Hoell, Jessica I; Morozov, Pavel et al. (2013) MicroRNAs in human cancer. Adv Exp Med Biol 774:1-20
Farazi, Thalia A; Brown, Miguel; Morozov, Pavel et al. (2012) Bioinformatic analysis of barcoded cDNA libraries for small RNA profiling by next-generation sequencing. Methods 58:171-87
Ascano Jr, Manuel; Mukherjee, Neelanjan; Bandaru, Pradeep et al. (2012) FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492:382-6
Hafner, Markus; Renwick, Neil; Farazi, Thalia A et al. (2012) Barcoded cDNA library preparation for small RNA profiling by next-generation sequencing. Methods 58:164-70
Ascano, Manuel; Hafner, Markus; Cekan, Pavol et al. (2012) Identification of RNA-protein interaction networks using PAR-CLIP. Wiley Interdiscip Rev RNA 3:159-77
Spitzer, Jessica I; Ugras, Stacy; Runge, Simon et al. (2011) mRNA and protein levels of FUS, EWSR1, and TAF15 are upregulated in liposarcoma. Genes Chromosomes Cancer 50:338-47

Showing the most recent 10 out of 15 publications