Collaborative Research: IntBIO: Micro level oxygen transport mechanisms in elite diving mammals: Capillary RBC to myofiber

合作研究：IntBIO：精英潜水哺乳动物的微水平氧运输机制：毛细血管红细胞到肌纤维

• 批准号: 2316378
• 负责人: William Tong
• 金额: $ 41.85万
• 依托单位: San Diego State University Foundation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2316378&HistoricalAwards=false
• 关键词: Collaborative; Research; IntBIO; Micro; level

For mammals, oxygen is essential to breathe and fuel daily activities. However, some marine mammals have specialized adaptations that allow them to spend long time periods underwater on a single breath. One adaptation that is not well understood is how red blood cells travel and oxygen is delivered to working muscles during a long duration dive. Further, not all marine mammals have evolved with the same adaptations and genes. One genetic difference is the loss of a gene that encodes for the enzyme CMP-Neu5AC hydroxylase in pinnipeds (e.g., sea lions) but not cetaceans (e.g., dolphins). CMP-Neu5AC hydroxylase modifies sugar residues coating the surface of cells, which could significantly affect oxygen transport. This project brings together a team of researchers with expertise in marine mammal biology, hemoglobin protein structure, spectroscopy, and cell and molecular biology to test the hypothesis that there are differences between pinnipeds and cetaceans in how oxygen-carrying red blood cells reach active skeletal muscles, how oxygen is unloaded from red blood cells and how oxygen is transferred across cell membranes. Unique training opportunities will be provided for next generation scientists as they perform experiments in diverse research settings and draw from several specialized fields to answer a complex biological question. By partnering with education development experts and training teachers who serve underrepresented students, we will integrate research-based content from our oxygen transport work on diving mammals into science lessons that meet Next Generation Science Standards and will be shared with teachers locally and nationally.O2 store management studies in air-breathing marine mammals demonstrate that diving mammals not only tolerate very low O2 environments, but actually thrive under these conditions. Part of their success derives from a well-defined dive response at the systemic level (bradycardia and vasoconstriction). However, O2 exchange at the peripheral microvessel-myocyte level is not well understood. Further, there may be differences in peripheral O2 transport due to the loss of a gene in pinnipeds but not cetaceans. This gene encodes for CMP-Neu5AC hydroxylase (CMAH) which alters cell surfaces including red blood cells, potentially affecting peripheral O2 transport. Our central hypothesis is that Pinnipeds and Cetaceans have distinct peripheral morphological adaptations and O2 regulatory mechanisms for extended diving. This hypothesis will be tested by investigators with complementary expertise in marine mammal biology, Hb/Mb protein structure, advanced spectroscopy/EPR, and cell/molecular O2 models using three approaches: 1. Evaluate and model in vivo O2 delivery in California sea lions (CaSL, Pinniped, Cmah-) and bottlenose dolphins (BD, Cetacean, Cmah+) during and immediately after a simulated dive. 2. Elucidate and model the biochemical mechanisms regulating RBC Hb-O2 off-loading kinetics in Pinnipeds and Cetaceans. 3. Elucidate O2 storage and diffusion parameters in CaSL and BD skeletal muscle endothelial cells +/- CMAH overexpression or sialic acid modulation. This project spans multiple organizational levels and will uncover adaptive mechanisms by which marine mammals push physiological limits during dives.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

对于哺乳动物来说，氧气对于呼吸和日常活动至关重要。然而，一些海洋哺乳动物具有特殊的适应能力，使它们能够在水下长时间呼吸。一种尚未被充分理解的适应是在长时间潜水期间红细胞如何移动以及氧气如何输送到工作肌肉。此外，并非所有海洋哺乳动物都具有相同的适应性和基因。一种遗传差异是鳍足类（例如海狮）而非鲸目动物（例如海豚）中编码 CMP-Neu5AC 羟化酶的基因缺失。 CMP-Neu5AC 羟化酶会修饰细胞表面的糖残基，这可能会显着影响氧运输。该项目汇集了一组在海洋哺乳动物生物学、血红蛋白蛋白质结构、光谱学以及细胞和分子生物学方面拥有专业知识的研究人员，以检验鳍足类动物和鲸类动物在携氧红细胞到达活跃骨骼肌的方式上存在差异的假设，氧气如何从红细胞中卸载以及氧气如何跨细胞膜转移。将为下一代科学家提供独特的培训机会，让他们在不同的研究环境中进行实验，并利用多个专业领域的知识来回答复杂的生物学问题。通过与教育发展专家和为代表性不足的学生提供培训的教师合作，我们将把潜水哺乳动物氧气运输工作中基于研究的内容整合到符合下一代科学标准的科学课程中，并将与当地和全国的教师共享。对呼吸空气的海洋哺乳动物的管理研究表明，潜水哺乳动物不仅能忍受极低的氧气环境，而且实际上在这些条件下茁壮成长。他们的成功部分源于系统层面明确的潜水反应（心动过缓和血管收缩）。然而，外周微血管-肌细胞水平的氧气交换尚不清楚。此外，由于鳍足类而非鲸类中基因的缺失，外周 O2 运输可能存在差异。该基因编码 CMP-Neu5AC 羟化酶 (CMAH)，它会改变包括红细胞在内的细胞表面，可能影响外周 O2 运输。我们的中心假设是鳍足类动物和鲸类动物具有不同的外周形态适应和用于长时间潜水的氧气调节机制。这一假设将由在海洋哺乳动物生物学、Hb/Mb 蛋白质结构、先进光谱/EPR 和细胞/分子 O2 模型方面具有互补专业知识的研究人员使用三种方法进行测试： 1. 评估和模拟加州海狮的体内 O2 输送（ CaSL、鳍足类、Cmah-) 和宽吻海豚（BD、鲸类、Cmah+）在模拟潜水期间和之后立即进行。 2. 阐明并模拟调节鳍足类和鲸类红细胞 Hb-O2 卸载动力学的生化机制。 3. 阐明 CaSL 和 BD 骨骼肌内皮细胞 +/- CMAH 过度表达或唾液酸调节中的 O2 储存和扩散参数。该项目跨越多个组织层面，将揭示海洋哺乳动物在潜水期间突破生理极限的适应机制。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。