NDRGs as mediators of hypoxia adaptation

PROJECT SUMMARY Oxygen is essential for the life of many organisms, as it used during aerobic respiration to generate cellular energy in the form of adenosine triphosphate (ATP). Low oxygen (whether caused by environmental or cellular hypoxia) prevents adequate ATP production and can consequently cause cell death. Paradoxically, excessive

oxygen, which often occurs post-hypoxia, is equally damaging, due to a surge in reactive oxygen species (ROS) that is damaging to biomolecules. Hence, aerobic organisms such as humans are susceptible to fluctuations in oxygen levels, which is manifested in many disease states, including chronic kidney disease,

acute kidney injury, sickle cell anemia and stroke. Stroke alone was the 5th leading cause of death in the US in 2017. Thus, an understanding of how cells can adapt to changes in environmental oxygen under different circumstances, and how this response can be manipulated therapeutically, is a major challenge for improving

human health. Despite the pathology caused by low O2, evolutionarily conserved mechanisms exist that protect organisms from hypoxic injury. One such mechanism is metabolic suppression, which involves the downregulation of energy-demanding processes to match reduced ATP production. The signaling pathways

that trigger and maintain metabolic suppression are mostly unknown. The Brewster laboratory recently uncovered a novel role for the adapter protein N-myc Downstream Regulated Gene 1a (Ndrg1a) in promoting long-term adaptation to anoxia (zero oxygen) in the zebrafish embryo via metabolic suppression. The specific

aims of this proposal are to deepen our mechanistic understanding of how Ndrg1 functions. Specifically, we will: (1) Uncover how Ndrg1 regulates trafficking of the sodium-potassium ATP-ase (NKA) pump in response to anoxia and re-oxygenation; (2) Investigate the broader function of Ndrg1a and Ndrg3a in hypoxia adaptation;

(3) Determine whether lactate is necessary and sufficient to prime cells for anoxia survival. In addition to these research goals, the PI will leverage the University of Maryland Baltimore County's outstanding commitment to Inclusive Excellence and her own position as the Director of the Graduate Research Training Initiative for Student Enhancement (G-RISE) Program to enhance the recruitment and

retention of PhD students from historically underrepresented (HUR) groups at UMBC and will train HUR students at all levels in hypoxia research in her laboratory. These students will be an integral part of her research group; will work on independent projects and author publications.