Grant: Discovery Grants Program - Individual

The control of breathing and uptake of oxygen by respiratory organs (e.g. lungs, gills, skin) is critical for survival in all vertebrates, from fish to humans. Specialized cells, called oxygen chemoreceptors, detect low oxygen (hypoxia) and initiate a cascade of events that ultimately leads to physiological changes, such as an increase in breathing. Previous studies have described these cells in mammals, but many of the events between the sensing of hypoxia and initiation of hyperventilation remain controversial. Furthermore, oxygen chemoreceptors are poorly defined in virtually all other animals on Earth. My research uses zebrafish and goldfish as convenient model systems to explore these processes. In addition, some vertebrates, such as fish, have evolved the incredible ability to withstand a complete lack of oxygen (anoxia)-a feat generally not possible in mammals-where even the central nervous system (CNS) is protected from permanent damage. But how specific networks of the CNS are protected during anoxia remains obscure. The long-term vision of my research is to demonstrate how vertebrates sense and survive hypoxia, and to shed light on how adaptations for survival have evolved. This Discovery Grant application addresses two main hypotheses: (i) within respiratory organs in fish, chemoreceptors sense hypoxia by virtue of complex interactions with sensory neurons via neurotransmission; and (ii) as a means of promoting survival, cell turnover and regeneration in the gills enhances respiration, whereas specialized networks of the CNS, such as the visual system, undergo coordinated interactions to preserve function. Young scientists will develop their careers and train in a dynamic and inclusive environment, with access to state-of-the-art resources. Highly qualified personnel (HQP) will be challenged to develop their skills in high-resolution microscopy, cellular physiology, molecular biology and single-cell RNA-sequencing, a relatively new and powerful technique to study gene expression. My proposed budget aims to increase my HQP training for 2024-2029 (up from 39 over the last grant cycle). My lab's integrative research program will develop new research tools and make novel contributions to the fields of Neurobiology and Comparative Physiology. Few labs integrate the techniques that we do, giving my HQP an edge internationally. The proposed studies will establish the first complete working model of oxygen sensing in non-mammalian vertebrates, and decipher the complex mechanisms that animals use to survive extreme hypoxia. As Director of the Cellular Imaging and Cytometry Facility, the tools we develop will be translated directly to more than 100 additional students each year. Furthermore, the knowledge we generate will be made freely available, through open-access publication and posting of transcriptomic data, to specialists in the biomedical community interested in respiratory dysfunction, brain ischemia and regenerative medicine.