Collaborative Research: Effects of Developmental Hypoxia on Juvenile Cardiac Function

合作研究：发育性缺氧对青少年心脏功能的影响

• 批准号: 1755253
• 负责人: Michael Hedrick
• 金额: $ 9万
• 依托单位: California State University, East Bay Foundation, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1755253&HistoricalAwards=false
• 关键词: Collaborative; Research; Effects; Developmental; Hypoxia

This collaborative project will investigate the outcome of low environmental oxygen levels (hypoxia) experienced during early development on the cardiovascular system of the American alligator, a species that naturally experiences low oxygen during embryonic life. The cardiovascular system is essential for the distribution of oxygen and metabolic fuels to active tissues. In some developing vertebrates, including humans, the function of the immature cardiovascular system can be negatively affected by environmental challenges such as low oxygen, and these changes can adversely affect the health of the adult. By contrast, species that naturally experience low oxygen during development, such as alligators, can benefit later in life from the changes to the cardiovascular system resulting from developmental hypoxia. Cardiovascular function will be assessed in two-year-old juvenile American alligators that were exposed to hypoxia as embryos, under active conditions (while exercising and after feeding). An integrative assessment will be conducted from the level of individual proteins to that of the whole animal. The broader impacts of the project include a significant number of opportunities for training students at multiple education levels in skills relevant to biomedical research, which will have a direct impact on the future work force, and training and practice in communicating science to the public. Developmental plasticity is a phenomenon that enables multiple environmentally mediated phenotypes to be generated from a single genotype. This plasticity, which is present in all multicellular taxa, can result in beneficial or adaptive changes that enhance function during juvenile and adult life. Hypoxia is an ecologically relevant environmental condition that, if encountered during embryonic life when organ systems are developing, can result in altered juvenile phenotypes that can impact organismal performance and affect animal fitness. Despite the important role hypoxia plays in causing phenotypic change, fundamental questions remain regarding the long-term effects of developmental hypoxia in vertebrates. This project investigates the impact of hypoxia experienced during a critical period of development on cardiovascular function of juvenile alligators at multiple levels of biological organization: from whole-animal performance, to functional studies of the cardiovascular system, to the organ, cellular, protein, and gene levels of organization. Alligators will be studied because they can naturally experience hypoxia during development and as adults. This approach will establish links between molecular and cellular traits, including changes in expression of genes involved in calcium dynamics and in cardiomyocyte contractility that underpin differences in cardiac output at the whole organism level. This multi-level approach will provide a comprehensive understanding of how embryonic hypoxia impacts cardiovascular function, with applicability to other vertebrate systems. The research findings will provide basic information that will be needed to make informed animal management decisions in the era of global climate change, and could lead to future treatment options for cardiovascular disease states. The project involves research training of graduate students and undergraduate students recruited from groups under-represented in science, as well as outreach to K-12 students and the general public.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.

这个合作项目将调查在美国短吻鳄的心血管系统早期发育过程中经历的低环境氧水平（缺氧）的结果，这是一种在胚胎期自然经历低氧的物种。心血管系统对于将氧气和代谢燃料分配到活性组织是必不可少的。在一些发育中的脊椎动物中，包括人类，未成熟的心血管系统的功能可能会受到环境挑战的负面影响，例如低氧，这些变化可能会对成年人的健康产生不利影响。相比之下，在发育过程中自然经历低氧的物种，如短吻鳄，可以在以后的生活中受益于发育缺氧引起的心血管系统的变化。心血管功能将在2岁的幼年美洲短吻鳄中进行评估，这些短吻鳄在胚胎时暴露于缺氧环境中，处于活跃状态（运动时和进食后）。将从单个蛋白质水平到整个动物水平进行综合评估。该项目更广泛的影响包括为在多个教育层次培训学生与生物医学研究相关的技能提供大量机会，这将对未来的劳动力产生直接影响，以及在向公众传播科学方面的培训和实践。发育可塑性是一种能够从单一基因型产生多种环境介导的表型的现象。这种可塑性存在于所有多细胞类群中，可以导致有益的或适应性的变化，增强幼年和成年生活中的功能。缺氧是一种与生态相关的环境条件，如果在器官系统发育的胚胎期遇到，可能会导致幼年表型改变，从而影响生物体的性能并影响动物的健康。尽管缺氧在引起表型变化中起着重要作用，但关于脊椎动物发育缺氧的长期影响仍然存在根本性问题。该项目调查了在发育的关键时期经历的缺氧对青少年扬子鳄心血管功能的影响，在多个生物组织水平：从整个动物的性能，心血管系统的功能研究，组织的器官，细胞，蛋白质和基因水平。短吻鳄将被研究，因为它们在发育过程中和成年后会自然地经历缺氧。这种方法将建立分子和细胞性状之间的联系，包括参与钙动力学和心肌细胞收缩性的基因表达的变化，这些基因表达的变化是整个生物体水平心输出量差异的基础。这种多层次的方法将提供一个全面的了解胚胎缺氧如何影响心血管功能，适用于其他脊椎动物系统。研究结果将提供在全球气候变化时代做出明智的动物管理决策所需的基本信息，并可能导致心血管疾病状态的未来治疗选择。该项目包括从科学代表性不足的群体中招募的研究生和本科生的研究培训，以及对K-12学生和普通公众的推广。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。