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

威德尔海豹是潜水冠军哺乳动物。这些动物的生理机能使它们能够维持长时间的屏住呼吸，并在深海潜水的极端压力下存活下来，这使它们能够在冰冷的南极水域茁壮成长。屏气潜水的生理特点的关键因素是它们对心脏和血管系统的显著调节能力，根据代谢需求协调血压和特定身体区域的流量，以及它们维持无氧期的能力。确定这些策略的细节具有巨大的潜力，可以更好地为人类医学提供信息，帮助我们开发心血管创伤（例如中风、心脏病发作）和与组织缺氧相关的疾病（例如肺炎、败血症或癌症）的新疗法。该项目的目标是记录控制海豹心血管调节的特定基因，并将其丰度和活动与人类进行比较。具体来说，研究人员将研究协调局部血流的信号通路。他们还将使用组织样本从威德尔海豹中培养细胞，这些细胞可用于研究实验室低氧条件下的分子效应。该项目将进一步实现国家科学基金会培养新一代科学家和使科学发现向公众开放的目标。该项目将培训一名兽医预科学生研究员，并通过社区健康改善中心、多元文化事务办公室和公共水族馆进行公共宣传。本研究的目的是揭示潜水反应的分子机制。潜水反应的一个标志是组织特异性血管系统调节，可能是由神经输入和血管细胞产生的局部信号分子的变化引起的。研究人员将利用新出现的基因组信息，开始解开潜水时血液循环重新分配的遗传学基础。他们还将直接验证一个假设，即信号系统的改变可以防止低氧条件下局部血管的变化，从而允许中央介导的潜水反射超越局部生理反应，并控制威德尔海豹血管壁的收缩。他们将对威德尔海豹组织进行rna测序，并利用结果序列，以及来自其他哺乳动物（如狗）的信息，获得威德尔海豹现有基因组组装的完整注释（根据参考基因组的命名特征识别所有基因），促进比较和物种特异性基因组研究。他们还将产生威德尔海豹多能干细胞系，这将成为细胞生物学家、分子生物学家和生理学家的一个有价值的研究工具，使他们能够进一步验证他们的假设。预计拟议的研究将推进我们对威德尔海豹在南极环境中茁壮成长的生化和生理适应的认识。

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.