All organisms must maintain homeostasis in the face of changing environmental conditions to survive. Unfortunately, physiological changes associated with aging decrease the capacity to maintain homeostasis, increasing susceptibility to disease, injury and infection. Hydrogen sulfide (H2S), which is naturally produced by animal cells, increases lifespan and thermotolerance in C. elegans. This proposal is related to my long- term goal to lead an independent research group that aims to understand the mechanistic basis of H2S effects in animals. The training provided by this award will allow me to develop lab management skills, publish research results and initiate a search for an independent position. In addition, the research plan will help me develop important skills using cytological and genetic techniques essential to fully utilize the power of the C. elegans system. In the first aim, I 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, I will identify genes and pathways involved in the response to H2S. I will characterize mutations that constitutively express H2S-induced phenotypes, and determine which act in concert with sir-2.1 to influence lifespan. In a complementary approach, I will evaluate the role of genes identified in an RNAi-based screen that, like sir-2.1, are required for H2S-induced changes. Finally, I will use a microarray approach to identify factors affected by H2S-induced changes that are correlated with increased lifespan. These experiments will uncover molecular mechanism(s) by which H2S influences lifespan. Dr. Mark Roth's lab is an excellent training environment for my career development, owing to past success using cell biological and genetic analysis to understand biological processes in C. elegans. Moreover, the Roth lab has demonstrated that H2S has profound effects on mammalian physiology that can improve survival in changing conditions.
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 increases lifespan in C. elegans. These studies may help explain processes that contribute to age- associated physiological decline that reduce the capacity to survive in a constantly fluctuating environment, which contribute increased mortality associated with aging.
|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|