We study how genes control life processes in homeostasis and organismic responses to extreme physical chemical conditions. Low temperature (hypothermia) and reduced oxygen (hypoxia) pervasively affect cellular metabolism and physiology, decelerate organismic biological time and trigger instinctive animal behaviors. Many species in nature have evolved unique traits to respond and adapt to severe hypothermia/hyperthermia/hypoxia. We use 1) genetically tractable C. elegans mutants isolated from large-scale screens with abnormal behavioral and extremophile-like phenotypes and 2) Mangrove Killifish, the only known self-fertilizing vertebrate with genetics similar to that of C. elegans and known extreme physiological phenotypes, as discovery tools. We also culture mammalian neural stem cells ex vivo from hibernating ground squirrels to unravel cellular intrinsic mechanisms of hypoxia/hypothermia tolerance.
With multidisciplinary approaches and technologies, our long-term goal is to understand how animals integrate interoceptive states with environmental stimuli through nervous/vascular/respiratory systems to coordinate internal homeostasis and tolerance of severe abiotic stresses. This will identify new mechanisms of extreme physiology and general principles of biological adaptation, with potential applications in organ transplantation, reversible cryo-preservation and novel therapeutics to treat metabolic, neurological and ischemic disorders.
Main projects include:
Discovering Novel Conserved Mechanisms for Animal Response to Hypoxia and Reoxygenation
Deprivation of oxygen and subsequent reoxygenation cause pathological responses in many disorders, including ischemic stroke, heart attacks, angina (chest pain), reperfusion injury and inflammatory pain. How animals use molecules and cells to sense tissue hypoxia and reoxygenation during ischemia and reperfusion pain and prevent injury are long-standing questions of key biomedical importance. We have used the nematode C. elegans to study responses to oxygen deprivation and restoration and discovered a behavior called the O2-ON response (hyperactivity triggered by reoxygenation, see Figure below and a Movie) that models key aspects of mammalian tissue response to reperfusion injury and inflammatory pain (Ma et al. 2012 Neuron; Ma et al. 2013 Science). From unbiased genetic screens, we identified a novel evolutionarily conserved pathway that controls this behavior.
The O2-ON response is driven by cytochrome P450 oxygenase-generated eicosanoids (known mammalian inflammatory pain mediators and potent vascular modulators) during reoxygenation and reflects aversive behavioral response to pain-like sensing of tissue reoxygenation. We aim to identify the still unknown receptors for cytochrome P450-generated EET-type encosanoids, to elucidate their mechanisms of action in behavior and extend C. elegans studies to mammals to determine roles of key homologous genes in mouse models of ischemic diseases (stroke and heart attack).
In addition, we are developing a strategy using both C. elegans and human cells to identify pathways and functions of novel conserved genes with proof-of-concept analysis of several genes related to human ischemic and neuro-inflammatory disorders. The strategy takes advantage of C. elegans in highly saturated mutagenesis screens, and combines this classic approach with modern RNA-seq and CRISPR technologies and should help lay the foundation for understanding disease mechanisms and identifying new therapeutic targets.
Genetic Screens for Novel Interoceptive Receptors
How animals sense internal physiological states (interoception) to maintain homeostasis remains a largely uncharted territory in biology. Key questions concerning the molecular and neural basis of interoception remain unanswered. For example, how changes in levels of specific nutrients, blood pressure and oxygen in the body are detected by sensory molecules and circuits is still largely unknown.
We are performing unbiased mutagenesis screens in C. elegans and Mangrove Killifish (the "Vertebrate C. elegans" that is similarly self-fertilizing) to identify novel genes and pathways that mediate homeostatic responses to changes in temperature, levels of oxygen and nutrients, key components for cellular energetics. We are currently focusing on a number of novel conserved transmembrane and membrane-less organelle proteins that likely constitute receptors or components of sensing machineries for key physiological cues and modulators.
Mammalian Models to Understand Mechanisms of Innate Tolerance to Ischemia-reperfusion Injury
The ground squirrel Spermophilus tridecemlineatus and their isolated adult neural stem cells in culture are highly tolerant of hypoxia-reoxygenation; the tolerance likely helps them to cope with low oxygen during hibernation. In mice, there are striking natural variations between different strains (e.g. SWR vs 129sv) in hypoxia perception and susceptibility to ischemia-reperfusion injury. The underlying genetic basis is largely unknown. We are interested in developing these rodent models (both in vivo and in cell culture) to identify novel mechanisms of tolerance to ischemic reperfusion injury.