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.
Beneficial 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 has dramatic 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 genes and pathways mediate the short and long-term physiological response to H2S?
2. How are cellular processes modulated by adaptation to H2S?
3. What is the mechanistic relationship between adaptation to H2S and responses to hypoxia?
Adaptations to survive hypoxia
All animals (with one notable exception!) require O2 to survive. Decreased O2 availability (hypoxia) can lead to cellular damage and death. The damaging effects of hypoxia contribute to many human pathologies, such as cardiovascular disease, stroke, and ischemia/reperfusion injury. However, some animals can tolerate even severe hypoxia quite well. For instance, C. elegans can enter into a state of suspended animation and survive in the complete absence of O2 (anoxia) for over 24 h! In suspended animation, embryogenesis arrests and all observable life processes halt. But when O2 is returned to the environment, the worms re-animate and continue none the worse for wear.
If there is just a little bit of O2 in the environment, worms do not enter into suspended animation. In fact, there are some very low concentrations of O2 that can kill C. elegans embryos. Curiously, we found that these concentrations of O2 are not lethal just a few hours later when the worms had just hatched. Instead, the larvae exposed to these specific hypoxic conditions enter a hypoxia-induced diapause. In these conditions, the animals continue to move but post-embryonic development reversibly arrests. Even more surprising, we observed that embryos in the uterus of diapausing adults enter into suspended animation and survived in the otherwise lethal conditions! We have identified neuronal factors that control what concentrations of O2 can induce hypoxia-induced diapause. Our working model is that the adult perception of hypoxia elicits a neuroendocrine signal that can suspend embryogenesis to allow the animal to find more favorable conditions.
We are also exploring other aspects of the physiological response to hypoxia, including effects on protein homeostasis. Protein homeostasis is the coordination of protein production, quality control and turnover. Defects in protein homeostasis are associated with many human disease states, including neurodegenerative diseases such as Huntington’s and Altzheimer’s.
Ongoing hypoxia projects:
1. How do neuronal circuits and signals regulate diapause?
2. What are the systemic signals that can regulate development and animation?
3. What genes and pathways are involved in diapause?
4. How does hypoxia influence protein homeostasis?
This is a picture of the same worm before and after exposure to hypoxia. The arrows mark embryos that enter into hypoxia-induced diapause.