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

揭示潜水反应的基因组和分子基础：威德尔海豹中的一氧化氮信号传导和血管调节

• 批准号: 1443554
• 负责人: Allyson Hindle
• 金额: $ 74.96万
• 依托单位: Massachusetts General Hospital
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1443554&HistoricalAwards=false
• 关键词: Unraveling; Genomic; Molecular; Basis; Dive

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.

威德尔海豹是潜水哺乳动物中的冠军。允许这些动物维持长时间屏气并在深潜的极端压力下生存的生理学使它们能够在冰冷的南极水域中繁衍生息。屏气潜水的生理特化的关键要素是他们能够显着调整心脏和血管系统，根据代谢需求协调血压和流向特定身体区域的能力，以及维持无氧时期的能力。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，帮助我们开发针对心血管创伤（例如中风、心脏病）和与组织供氧减弱相关的疾病（例如肺炎、败血症或癌症）的新疗法。该项目的目标是记录海豹中控制这些心血管调节的特定基因，并将其丰度和活性与人类进行比较。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产生培养细胞，这些细胞可用于研究实验室低氧条件的分子影响。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向公众提供科学发现的目标。该项目将培训一名兽医预科学生研究员，并将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。这项研究的目的是揭示潜水反应背后的分子机制。潜水反应的一个标志是组织特异性血管系统调节，这可能是由于神经输入和血管细胞产生的局部信号分子产生的变化造成的。研究人员将利用新出现的基因组信息来揭开潜水过程中循环重新分布的遗传学基础。他们还将直接测试信号系统的修改可防止低氧条件下局部血管变化的假设，从而允许中枢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，并使用所得序列以及来自其他哺乳动物（例如狗）的信息，获得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）。威德尔印章，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，这对于细胞生物学家、分子生物学家和生理学家来说应该是一个有价值的研究工具，使他们能够进一步检验他们的假设。预计拟议的研究将增进我们对生化和生理适应的了解，使威德尔海豹在南极环境中繁衍生息。

项目成果

Intrinsic anti-inflammatory properties in the serum of two species of deep-diving seal

两种深潜海豹血清的内在抗炎特性

• DOI: 10.1242/jeb.178491
• 发表时间: 2018-07-01
• 期刊: Journal of Experimental Biology
• 影响因子: 2.8
• 作者: A. Bagchi;A. Batten;M. Levin;Kaitlin N. Allen;M. Fitzgerald;Luis A. Hückstädt;D. Costa;Emmanuel S. Buys;A. Hindle
• 通讯作者: A. Hindle

Low guanylyl cyclase activity in Weddell seals: implications for peripheral vasoconstriction and perfusion of the brain during diving

威德尔海豹的低鸟苷酸环化酶活性：对潜水期间外周血管收缩和大脑灌注的影响

• DOI: 10.1152/ajpregu.00283.2018
• 发表时间: 2019-05
• 期刊: integrative and comparative physiology
• 作者: Hindle, Allyson G;Allen, Kaitlin N;Batten, Annabelle J;Hückstädt, Luis A;Turner;Schulberg, S Anne;Johnson, Jeremy;Karlsson, Elinor;Lindblad;Costa, Daniel P;et al
• 通讯作者: et al