The goal of research in the Miller Lab is to understand how animals maintain homeostasis and survive in changing conditions.
We use the nematode, C. elegans, to investigate the responses to small gaseous molecules, oxygen (O2) and hydrogen sulfide (H2S). These small molecules influence important biological functions, including development, metabolism and homeostasis. We aim to understand how responses to these external factors are integrated with each other and biology at the molecular, cellular and organismal level. Our studies will reveal new insight about the fundamental nature of the flexibility that enables animals to maintain homeostasis in the face of environmental, metabolic and physiological stress.
Physiological effects of adaptation to hydrogen sulfide
Although H2S is best known as a toxic gas with the smell of rotten eggs, it has recently become clear that H2S can also have beneficial effects on animal physiology. Mice exposed to H2S enter into a hibernation-like state, with decreased metabolism and low core body temperature. Mammals exposed to H2S can survive better in harsh conditions, especially when O2 is limiting.
We have used worms to begin to understand the molecular basis for the beneficial effects of H2S. We found that worms grown in low levels of H2S live 70% longer than untreated controls. We are now investigating how adaptation to H2S is integrated with cellular homeostasis pathways to improve survival in changing conditions.
Ongoing hydrogen sulfide projects:
1. What are the genes and pathways that mediate the short and long-term physiological response to H2S?
We are interested in cellular factors that mediate conserved effects of H2S exposure, and have a variety of genetic mutants that disrupt this process. Characterizing these mutants is revealing fundamental aspects of cellular physiology that are modulated by the response to H2S.
We are also working to understand how the response to H2S is coordinated between different tissues. We are currently working to characterize systemic signal that are required for the efficient response to H2S.
We expect that the results of these studies will lead to new insight into normal aging processes (that are modulated by H2S) and fundamental aspects of the response to H2S.
2. Epigenetic effects of exposure to H2S.
There are many situations where environmental conditions have long-lasting effects on animals. We have discovered that exposure to H2S leads to formation of an epigenetic bookmark that improves survival and facilitates the response to subsequent environmental changes. We are working to understand the mechanistic basis of H2S epigenetic bookmarking, focusing on how
3. What is the mechanistic relationship between adaptation to H2S and responses to hypoxia?
We have discovered that, just like in mammals, the effects of hypoxia are modulated by exposure to H2S in C. elegans. We believe that understanding the interaction between O2 and H2S will reveal new strategies to improve cell and animal survival in hypoxia.