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.

Weddell Seal是冠军潜水哺乳动物。允许这些动物维持呼吸延长时期并在深处潜水的极大压力中生存的生理学使它们能够在冰冷的南极水中繁衍生息。他们对呼吸潜水的生理学专业的关键要素是他们对心脏和血管系统进行显着调整的能力，根据其代谢需求协调血压和流向特定身体区域的流动，以及维持没有氧气的时期的能力。确定这些策略的细节具有更好地为人类医学提供信息的巨大潜力，帮助我们开发出新的心血管创伤疗法（例如，中风，心脏病发作）和与氧气递送到组织（例如肺炎，败血症或癌症）有关的疾病。该项目的目的是记录控制密封中这些心血管调整的特定基因，并将其丰度和活动与人类进行比较。具体而言，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品从Weddell密封中产生培养的细胞，这些细胞可用于研究实验室中低氧条件的分子效应。该项目将进一步培训新一代科学家的目标，并为公众提供科学发现。该项目将培训兽医前的学生研究人员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。这项研究的目的是阐明潜水反应的分子机制。潜水反应的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的产生而产生的。研究人员将使用新兴的基因组信息开始揭示潜水过程中循环重新分布的遗传学。他们还将直接检验以下假设：信号系统中的修饰可防止局部血管在低氧气条件下的变化，从而允许中心介导的潜水反射覆盖局部生理反应，并控制Weddell密封中血管壁的收缩。他们将执行Weddell密封组织的RNA序列，并使用所得的顺序以及来自其他哺乳动物（例如狗）的信息，以获取针对Weddell密封的现有基因组组装的完整注释（基于参考基因组的命名特征，识别所有基因），促进了比较和物种特异性的基因组研究。他们还将生成Weddell密封多能干细胞系，该干细胞系应该是细胞生物学家，分子生物学家和生理学家的宝贵研究工具，该工具将使他们能够进一步检验其假设。预计拟议的研究将促进我们对生化和生理适应的了解，这些适应使韦德尔密封在南极环境中蓬勃发展。

项目成果

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

• 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: Bagchi, Aranya;Batten, Annabelle J.;Hindle, Allyson G.
• 通讯作者: Hindle, Allyson G.

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

• DOI: 10.1152/ajpregu.00283.2018
• 发表时间: 2019-06-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
• 影响因子: 2.8
• 作者: Hindle, Allyson G.;Allen, Kaitlin N.;Buys, Emmanuel S.
• 通讯作者: Buys, Emmanuel S.