Recent studies suggest that the regulation of longevity may be conserved in many eukaryotes ranging from yeast to mammals. In this project, we plan to obtain expression profiles on a time course for yeast strains with normal and extended life span, to develop novel statistical methods to detect expression differentiation, to develop new statistical and computational method to understand the pathways leading to extended life span, and to disseminate data and software resulting from the project. From microarray measurement, we seek differentiation of mRNA expressions among different biological samples. The statistical treatment of normalization aims to reduce army-specific """"""""block effect"""""""" due to uncontrolled variation. To adjust for spatial patterns in both background and scale, we propose sub-array normalization. According to our experimental design, substantial differentiation may exist among arrays and we detect them by the technique of least trimmed squares, whose exact solution can be computed by a fast and stable algorithm we developed recently. From microarray analysis of strains such as sch9? and ras2? mutants, those genes with significant differentiation will serve as seeds for future investigation. We will pursue several directions. First, we search for genes that are co-expressed with seeds. Second, we search for changes of m-expressions associated with seeds. Third, we investigate regulation related to seed genes. Fourth, using the protein-protein interaction databases available for growing yeast we attempt to identify protein complexes as well as pathways that regulate longevity in yeast. Many genomic or interaction data such as protein-DNA interaction data can be arranged in a binary array. We introduce the structure of directed acyclic Boolean (DAB) networks as a tool of exploring biological pathways from binary arrays. With a few reasonable starting networks, we wilt use more sophisticated Bayesian networks to polish and refine the final results. This project aims to discover causations of life span extension from systematic experiments of yeast expression. To serve the scientific mission, we develop and integrate statistical and computational methodologies. Our research will benefit the society by new understanding of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM075308-01
Application #
6985611
Study Section
Special Emphasis Panel (ZGM1-CBCB-0 (BM))
Program Officer
Whitmarsh, John
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$260,000
Indirect Cost
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Fabrizio, Paola; Hoon, Shawn; Shamalnasab, Mehrnaz et al. (2010) Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation. PLoS Genet 6:e1001024
Fontana, Luigi; Partridge, Linda; Longo, Valter D (2010) Extending healthy life span--from yeast to humans. Science 328:321-6
Wei, Min; Fabrizio, Paola; Madia, Federica et al. (2009) Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. PLoS Genet 5:e1000467
Madia, Federica; Wei, Min; Yuan, Valerie et al. (2009) Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism. J Cell Biol 186:509-23
Cheng, Chao; Li, Lei M (2008) Inferring microRNA activities by combining gene expression with microRNA target prediction. PLoS One 3:e1989
Cheng, Chao; Li, Lei M (2008) Systematic identification of cell cycle regulated transcription factors from microarray time series data. BMC Genomics 9:116
Madia, Federica; Gattazzo, Cristina; Wei, Min et al. (2008) Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system. J Cell Biol 180:67-81
Wei, Min; Fabrizio, Paola; Hu, Jia et al. (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet 4:e13
Ge, Huanying; Cheng, Chao; Li, Lei M (2008) A probe-treatment-reference (PTR) model for the analysis of oligonucleotide expression microarrays. BMC Bioinformatics 9:194
Cheng, Chao; Fabrizio, Paola; Ge, Huanying et al. (2007) Significant and systematic expression differentiation in long-lived yeast strains. PLoS One 2:e1095

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