This application describes a 4 year training program for the development of an academic career in Geriatrics with a research focus on the basic Biology of Aging. The principal investigator has completed clinical training in Geriatrics and is now pursuing research using the free-living nematode, C. elegans, to study the genetic regulation of aging and lifespan determination. The training program consists of structured didactic work and mentored research experiences designed to build upon the principal investigator's prior research experience in the areas of molecular biology and fruit fly, Drosophila, genetics. Specifically the program will develop new research abilities in the areas of Biology of Aging, C. elegans genetics, Biology of Dopamine, and Molecular Toxicology. ? ? The application also includes a research program which seeks to advance the understanding of aging through studies using the worm. Specifically, study will focus on the 4-hydroxyphenylpyruvate dioxygenase gene which is a target gene of the orphan nuclear hormone receptor daf-12. This gene is down-regulated in both long-lived daf-12 mutants and in long-lived daf-2 insulin/IGF-1 receptor mutants suggesting a role in the regulation of aging. Consistent with this, down-regulation of this single gene by RNAi extends worm lifespan by up to 30%. The mechanisms involved in the increase in longevity will be investigated in worms using a combination of RNA interference studies and genetics. It appears that tyrosine metabolites may be toxic to tissues and reduction of these metabolite levels may explain some or all of the extension of lifespan. A parallel investigation during the project will be to investigate whether the tyrosine-derived neurotransmitter dopamine may share common toxic effects on worms. ? ? The ultimate goal of the training program is to allow the principal investigator to develop a program in the basic Biology of Aging within a Geriatrics Division. An improved understanding of the biochemical events involved in aging and the responses of an organism to these events will greatly enhance our understanding of the aging process and the link between aging and disease. This understanding holds the potential for the development of treatments to address the negative consequences of aging or to prevent diseases associated with aging. Additionally, an improved understanding of the aging process will provide insight into the differences between geriatric patients and younger patients especially with regards to differences in disease symptoms and response to treatments. ? ? ?

National Institute of Health (NIH)
National Institute on Aging (NIA)
Clinical Investigator Award (CIA) (K08)
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Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (M1))
Program Officer
Wise, Bradley C
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Ferguson, Annabel A; Roy, Sudipa; Kormanik, Kaitlyn N et al. (2013) TATN-1 mutations reveal a novel role for tyrosine as a metabolic signal that influences developmental decisions and longevity in Caenorhabditis elegans. PLoS Genet 9:e1004020
Kashyap, Luv; Perera, Subashan; Fisher, Alfred L (2012) Identification of novel genes involved in sarcopenia through RNAi screening in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci 67:56-65
Powolny, Anna A; Singh, Shivendra V; Melov, Simon et al. (2011) The garlic constituent diallyl trisulfide increases the lifespan of C. elegans via skn-1 activation. Exp Gerontol 46:441-52
Zhang, Yue; Kashyap, Luv; Ferguson, Annabel A et al. (2011) The production of C. elegans transgenes via recombineering with the galK selectable marker. J Vis Exp :
Cai, Liquan; Phong, Binh L; Fisher, Alfred L et al. (2011) Regulation of fertility, survival, and cuticle collagen function by the Caenorhabditis elegans eaf-1 and ell-1 genes. J Biol Chem 286:35915-21
Hochbaum, Daniel; Zhang, Yue; Stuckenholz, Carsten et al. (2011) DAF-12 regulates a connected network of genes to ensure robust developmental decisions. PLoS Genet 7:e1002179
Hochbaum, Daniel; Ferguson, Annabel A; Fisher, Alfred L (2010) Generation of transgenic C. elegans by biolistic transformation. J Vis Exp :
Ferguson, Annabel A; Springer, Mitchell G; Fisher, Alfred L (2010) skn-1-Dependent and -independent regulation of aip-1 expression following metabolic stress in Caenorhabditis elegans. Mol Cell Biol 30:2651-67
Takayama, Mariko; Fujita, Rie; Suzuki, Mikiko et al. (2010) Genetic analysis of hierarchical regulation for Gata1 and NF-E2 p45 gene expression in megakaryopoiesis. Mol Cell Biol 30:2668-80
Ferguson, Annabel A; Fisher, Alfred L (2009) Retrofitting ampicillin resistant vectors by recombination for use in generating C. elegans transgenic animals by bombardment. Plasmid 62:140-5

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