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: 2316377
• 负责人: ellen breen
• 金额: $ 136.32万
• 依托单位: University of California-San Diego
• 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=2316377&HistoricalAwards=false
• 关键词: Collaborative; Research; IntBIO; Micro; level

For mammals, oxygen is essential for life. 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 storage 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. It advances knowledge of the cellular mechanisms that enable mammalian survival in low oxygen environments.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，氧气是生命的必需品。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。一个不太清楚的适应是红细胞如何旅行，氧气如何在长时间潜水期间输送到工作肌肉。此外，并非所有的海洋哺乳动物都进化出相同的适应性和基因。一个遗传差异是在鳍足类中编码酶CMP-Neu 5AC羟化酶的基因的丢失（例如，海狮）而不是鲸类动物（例如，海豚）。CMP-Neu 5AC羟化酶修饰覆盖细胞表面的糖残基，这可能显著影响氧转运。该项目汇集了一组具有海洋哺乳动物生物学，血红蛋白蛋白结构，光谱学以及细胞和分子生物学专业知识的研究人员，以测试以下假设：鳍足类和鲸目动物之间在携氧红细胞如何到达活跃的骨骼肌，氧气如何从红细胞中卸载以及氧气如何通过细胞膜转移方面存在差异。将为下一代科学家提供独特的培训机会，因为他们在不同的研究环境中进行实验，并从几个专业领域中汲取经验，以回答复杂的生物学问题。通过与教育发展专家和培训教师合作，为代表性不足的学生提供服务，我们将把我们在潜水哺乳动物氧气运输工作中的研究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分享。而是在这种条件下茁壮成长他们的成功部分来自于系统水平的明确的潜水反应（心动过缓和血管收缩）。然而，在外周微血管-肌细胞水平的O2交换还没有很好的理解。此外，由于鳍足动物基因的缺失，外周O2转运可能存在差异，但鲸类动物则不然。该基因编码CMP-Neu 5AC羟化酶（CMAH），其改变包括红细胞在内的细胞表面，可能影响外周O2转运。我们的中心假设是，鳍足类和鲸类动物有不同的外围形态适应和O2的调节机制，延长潜水。这一假设将由具有海洋哺乳动物生物学、Hb/Mb蛋白质结构、高级光谱学/EPR和细胞/分子O2模型方面互补专业知识的研究人员使用三种方法进行测试：1.在模拟潜水期间和之后立即评估和模拟加州海狮（CaSL，鳍足类，Cmah-）和白海豚（BD，鲸类，Cmah+）的体内O2输送。2.阐明和模拟生物化学机制调节红细胞Hb-O2卸载动力学在鳍足类和鲸类动物。3.阐明CaSL和BD骨骼肌内皮细胞+/- CMAH过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过程中推动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。