Unraveling the Genomic and Molecular Basis of the Dive Response: Nitric Oxide Signaling and Vasoregulation in the Weddell Seal

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The Weddell seal is a champion diving mammal. The physiology that permits these animals to sustain extended breath-hold periods and survive the extreme pressure of diving deep allows them to thrive in icy Antarctic waters. Key elements of their physiological specializations to breath-hold diving are their ability for remarkable adjustment of their heart and blood vessel system, coordinating blood pressure and flow to specific body regions based on their metabolic requirements, and their ability to sustain periods without oxygen. Identifying the details of these strategies has tremendous potential to better inform human medicine, helping us to develop novel therapies for cardiovascular trauma (e.g. stroke, heart attack) and diseases associated with blunted oxygen delivery to tissues (e.g. pneumonia, sepsis, or cancer). The goal of this project is to document specific genes that control these cardiovascular adjustments in seals, and to compare their abundance and activity with humans. Specifically, the investigators will study a signaling pathway that coordinates local blood flow. They will also use tissue samples to generate cultured cells from Weddell seals that can be used to study the molecular effects of low oxygen conditions in the laboratory. The project will further the NSF goals of training new generations of scientists and of making scientific discoveries available to the general public. The project will train a pre-veterinary student researcher will conduct public outreach via a center for community health improvement, a multicultural affairs office, and a public aquarium. The goal of this study is to unravel the molecular mechanisms underlying the dive response. A hallmark of the dive response is tissue-specific vascular system regulation, likely resulting from variation in both nerve inputs and in production of local signaling molecules produced by blood vessel cells. The investigators will use emerging genomic information to begin to unravel the genetics underlying redistribution of the circulation during diving. They will also directly test the hypothesis that modifications in the signaling system prevent local blood vessel changes under low oxygen conditions, thereby allowing the centrally mediated diving reflex to override local physiological responses and to control the constriction of blood vessel walls in Weddell seals. They will perform RNA-sequencing of Weddell seal tissues and use the resulting sequence, along with information from other mammals such as dog, to obtain a full annotation (identifying all genes based on named features of reference genomes) of the existing genome assembly for the Weddell seal, facilitating comparative and species-specific genomic research. They will also generate a Weddell seal pluripotent stem cell line which should be a valuable research tool for cell biologists, molecular biologists and physiologists that will allow them to further test their hypotheses. It is expected that the proposed studies will advance our knowledge of the biochemical and physiological adaptations that allow the Weddell seal to thrive in the Antarctic environment.