Embryonic Transitions in Vertebrate Cardiovascular Physiology - II

这个奖项将扩展我们目前对心血管调节发展的高度有限的理解，以及它在脊椎动物胚胎中的潜在可塑性。这个为期四年的项目将集中在三个研究领域，使用传统的发育模型（斑马鱼的鱼苗，鸡的胚胎），以及其他鱼类和鸟类的胚胎。第一个领域扩展了PI对早期脊椎动物胚胎循环发育及其调控的调查，对血压、血流量和心率作为发育的功能进行定量测量，并在药理和环境操纵期间进行测量。特别是，这些研究将集中在两个目标上：1)确定胚胎发育期间心血管调节的变化。最近的研究结果表明，在控制循环的反射的发展中，出现和成熟的速度都是非线性的。鸡、鸸鹋和斑马鱼的胚胎之间正在出现主要的物种特异性差异。因此，有必要进行实验，以确定古老的鸡胚胎模型是否确实代表了脊椎动物的生理发育。2)禽绒毛膜-尿囊膜（CAM）血管特性的定量，这在很大程度上仍然是一个生理黑箱。由于CAM和胚胎血管是串联的，胚胎血管床的内在反应可能被CAM本身同时发生的不同血管直径的定性反应所掩盖，特别是当血压和其他测量仅在循环中的一个点进行时。第二个重点是鸟类胚胎在孵化后期的呼吸过渡，因为它在内部打头（将喙推进内部空气细胞），并放弃使用CAM呼吸而使用肺部呼吸。该奖项将资助研究鸡胚19-21天和鸸鹋胚50-53天生理变化的实验。迄今为止，PI的实验表明，这2-3天的周期对心血管调节具有强烈而复杂的变化，相对于哺乳动物的出生，其相对较慢的时间过程应该为心肺过渡提供重要的新见解。第三个领域将是研究环境（如缺氧）如何影响心血管系统的正常发育轨迹。特别是，计划中的实验将探索胚胎心血管系统在发育过程中表现出“自我修复”的程度。令人兴奋的新结果表明，在低氧环境中产生的早期代谢改变的胚胎可以沿着意想不到的轨迹发育，并且仍然达到正常的代谢状态。提出的研究计划将为科学进步和人力资源开发做出重要和及时的贡献。拟议的测量将提供基于机械的信息，了解心血管系统是如何发展的，它们如何对常见的环境压力做出强烈反应，以及在随后的发展过程中，它们的长期功能在多大程度上可能被环境改变。这些实验将产生对脊椎动物胚胎生理学的基本理解，这将对通过基因治疗和胚胎矫正手术（被一些人设想为下一个外科前沿）结合开发人类缺陷的矫正程序至关重要。该项目将培养一批新的本科生和研究生使用当代生理学技术来解决发展生理学中的关键问题。该项目将通过PI的非正式环境遗传和生长科学（EGGS）网络（来自6个国家的合作科学家）增加国际合作，并拓宽受训者的专业前景。最后，在高中和初中教师和学生中培养更大的对科学的热爱。从丹顿选出的中学教师将通过PI与当地学区的合作项目参与UNT的原创科学研究。

This award will extend our current highly limited understanding of the development of cardiovascular regulation, and its potential plasticity in vertebrate embryos. The four-year project will focus on three areas of study, using conventional developmental models (the fry of zebrafish Brachydanio rerio, embryos of chickens Gallus gallus), as well as embryos of other fishes and birds. The first area extends the PI's investigation of the development of the circulation and its regulation in early vertebrate embryos, making quantitative measurements of blood pressure, blood flow, and heart rate as a function of development, and during pharmacological and environmental manipulation. In particular, these studies will focus on two aims: 1) Determination of changes in cardiovascular regulation during embryonic development. Recent findings show that there are non-linear rates of both appearance and maturation in the development of reflexes controlling the circulation. Major species-specific differences are emerging between chicken, emu and zebrafish embryos. Thus experiments to determine whether the venerable chick embryo model is indeed representative of vertebrate physiological development are warranted. 2) Quantification of the specific properties of the blood vessels of the avian chorioallantoic membrane (CAM), which remains largely a physiological black box. Because the CAM and embryonic vessels are located in series, intrinsic responses of the vascular beds of the embryo could be muted or completely masked by qualitatively different vessel diameter responses occurring simultaneously in the CAM per se, especially when blood pressure and other measurements are made at only one point in the circulation.The second area focuses on the breathing transition in late incubation of the avian embryo as it internally pips (pushes its beak into the internal air cell) and relinquishes respiration using the CAM for respiration using the lungs. This award will fund experiments to characterize the physiological changes that occur from day 19-21 in chick embryos, and from Day 50-53 in emu embryos. The PI's experiments to date suggest that this 2-3 day period holds intense and complex change for cardiovascular regulation, and its relatively slow time course relative to mammalian birth should provide critical new insights in cardio-pulmonary transitions.The third area will be an investigation of how environment (e.g. hypoxia) influences normal developmental trajectories for the cardiovascular system. In particular, planned experiments will explore the extent to which embryonic cardiovascular systems exhibit "self-repair" as development progresses. Exciting new results suggest that embryos with modifications of metabolism in early development produced by low environmental oxygen can develop along unexpected trajectories and still arrive at a normal metabolic state.The proposed research program will make important and timely contributions to scientific advancement and human resource development. The proposed measurements will provide mechanistically-based information on how cardiovascular systems develop, how they respond acutely to common environmental stress, and to what extent their long-term function during subsequent development may be altered by environment. The experiments will yield a basic understanding of embryonic physiology in vertebrates which will be important in developing corrective procedures for human defects through a combination of gene therapy and embryonic corrective surgery (envisaged by some as the next surgical frontier). This project will train a new cohort of undergraduate and graduate students in the use of contemporary physiological techniques to address critical questions in developmental physiology. The project will increase international collaboration, and the broadening of professional vistas for trainees through the PI's informal Environmental Genetic and Growth Science (EGGS) network of collaborating scientists from six countries. And finally, a greater love of science in high school and middle school teachers and their students will be fostered. Selected secondary school teachers from Denton will participate in original scientific research at UNT, through the PI's collaborative program with the local school district.