All organisms must maintain homeostasis in the face of changing environmental conditions to survive. Physiological changes associated with ageing decrease the capacity to maintain homeostasis, increasing susceptibility to disease, injury and infection. As a postdoc with Dr. Mark Roth, Dr. Miller found that hydrogen sulfide (H2S), which is naturally produced by animal cells, increases lifespan and thermotolerance in C. elegans. In mammals, H2S improves survival in changing conditions. Thus, H2S may have a conserved function to improve the ability to maintain homeostasis. The purpose ofthe proposed research is to elucidate the mechanistic basis by which H2S modulates lifespan in C. elegans.
The first aim will test the hypothesis that H2S delays age-associated changes in C. elegans. These experiments will establish how H2S affects diverse biological processes in different tissue types. In the second aim, genes and pathways involved in the response to H2S will be identified. This work will utilize genetic tools developed by Dr. Miller as a postdoc. Mutant animals which express H2S-induced phenotypes will be characterized to determine whether they influence lifespan and/or other aging-associated phenotypes. Epistasis will be used to determine which act in concert with sir-2.1. In a complementary approach, 1 will evaluate the role of genes that, like sir-2.1, are required for H2S-induced changes. Finally, I will use a microarray approach to identify genes affected by H2S-induced changes and are correlated with increased lifespan. The proposed research will generate publications and preliminary data that will enable Dr. Miller to apply for an independent ROI research award within 24 months of her transition to independence.
Many conserved processes of aging have been identified by studying factors that influence lifespan in invertebrate models. This research program aims to identify the mechanism by which hydrogen sulfide affects lifespan in C. elegans. These studies may help explain beneficial effects of hydrogen sulfide in mammals and provide insight into the fundamental effects of age-associated physiological changes on homeostatic mechanisms
|Horsman, Joseph W; Miller, Dana L (2016) Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide. J Biol Chem 291:5320-5|
|Fawcett, Emily M; Hoyt, Jill M; Johnson, Jenna K et al. (2015) Hypoxia disrupts proteostasis in Caenorhabditis elegans. Aging Cell 14:92-101|
|Chapin, Hannah C; Okada, Megan; Merz, Alexey J et al. (2015) Tissue-specific autophagy responses to aging and stress in C. elegans. Aging (Albany NY) 7:419-34|
|Iranon, Nicole N; Miller, Dana L (2012) Interactions between oxygen homeostasis, food availability, and hydrogen sulfide signaling. Front Genet 3:257|
|Fawcett, Emily M; Horsman, Joseph W; Miller, Dana L (2012) Creating defined gaseous environments to study the effects of hypoxia on C. elegans. J Vis Exp :e4088|
|Miller, Dana L; Budde, Mark W; Roth, Mark B (2011) HIF-1 and SKN-1 coordinate the transcriptional response to hydrogen sulfide in Caenorhabditis elegans. PLoS One 6:e25476|