10/28/2015 - 12:15pm to 1:15pm
Dr. Scott Parks, Centre Scientifique de Monaco
Oxygen (O2) has played a dominant role in shaping biology resulting in cells and organisms that are finely tuned to their surrounding O2 levels. Reductions in O2(hypoxia) can thus have a significant impact on cellular homeostasis. Hypoxia is intriguing as it can have both positive and negative outcomes on cellular physiology. Particular attention in hypoxia research has been on the pathophysiology of tumor progression. Solid tumors develop alongside a chaotic and incomplete vasculature resulting in hypoxic zones for cells distant from a blood source. These hypoxic zones are associated with aggressive tumor cell behavior and following the discovery that the Hypoxia Inducible Factor (HIF) alters the transcription of many genes (>1000), intense focus has been placed on understanding the cellular mechanisms of hypoxia sensing and their resulting responses. Following years of elucidating the biochemistry and physiology of hypoxia sensors, my postdoctoral laboratory has been studying the role of hypoxia-regulated proteins, particularly in relation to cell metabolism. We have recently demonstrated that hypoxia promotes cell survival during acidosis via protection of cellular energy (ATP) levels. This mechanism incorporates numerous transporters at the cell membrane that respond to hypoxia to maintain glycolytic activity. I will present our findings from a series of studies arriving to a current overall model for hypoxia-regulated proteins that contribute to nutrient supply, utilization and waste removal (i.e. MCTs, LAT1, CAs, NBCs and NHE1).
A revolution in genomic editing has occurred in the past decade beginning with the use of zinc-finger nuclease (ZFN) technology followed by the development of TALEN and currently CRISPR-Cas9. We have thus transitioned our studies from performing gene interference (shRNA) to precise genomic editing. Our gene knockouts using CRISPR-Cas9 and ZFN for multiple proteins have revealed key data for understanding cellular signaling pathways that control metabolism in the hypoxic environment (i.e. AKT, NFkB). My goal is to use these genomic editing tools in future studies to precisely understand marine cellular physiology during hypoxia. Hypoxia is becoming a prominent factor in marine environments and an understanding of the cellular response to hypoxia is required to assess the ecological impact. I propose to investigate the evolutionary conservation of hypoxia sensing and tolerance in marine organisms drawing on the above-mentioned advances in genomic editing. A long term focus will be on hypoxia signaling in corals, which will be initiated using the Aiptasia and Nematostella model systems among others. Hypoxia induced changes in cellular metabolism will be assessed with an emphasis on O2 sensing (HIF, FIH, NFkB), nutrient supply (autophagy, amino-acid transport), nutrient utilization (cellular respiration vs. glycolysis) and growth control pathways (mTOR and AKT). These research themes will then be extended to applied physiology studies on important species along the California coast such as the Market Squid.
Dr. Parks is an MB faculty candidate.
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