Thyroid regulation of fish development: physiological, cellular and molecular responses with evolutionary considerations

本研究项目结合甲状腺激素生理学、分子生物学和基因调控的研究，破译七鳃鳗变态这一重大发育事件的内部信号。七鳃鳗的变态类似于鱼样蝌蚪变成青蛙的变态。七鳃鳗是现存最古老的脊椎动物（有脊柱的动物，包括人类）之一，是研究发育调节和脊椎动物祖先进化的良好模型。有趣的是，七鳃鳗变态的开始与甲状腺激素水平的急剧下降相吻合。这种下降与其他脊椎动物在重大发育事件开始时甲状腺激素水平的激增相反。本研究计划的目的是确定这种七鳃鳗变态的悖论是否代表了甲状腺激素控制七鳃鳗发育的根本差异（即基因调节），或者更简单地说是活性激素的生理和细胞调节的差异。具体来说，这个项目将破译以下发育过程中的功能和作用：a)七鳃鳗血液中运输甲状腺激素的系统；b)激活和灭活细胞中激素的酶；c)激素结合的受体，以调节基因活性。最后，我们还将确定由甲状腺激素控制并可能驱动变态的lamlampey基因。我的研究项目将促进我们对甲状腺激素的调节及其在古代脊椎动物发育中的作用的理解。甲状腺激素参与脊椎动物的发育、生长、脂肪代谢、体温调节、免疫防御和繁殖等重要生物过程。七鳃鳗甲状腺系统的独特性质及其在七鳃鳗发育中的作用可能为脊椎动物甲状腺生理和功能障碍提供新的见解。最后，更好地了解控制七鳃鳗发育的因素将为开发环境友好的措施提供新的机会，以控制五大湖的海七鳃鳗种群，减少我们对当前化学处理的依赖。

This research program combines studies in thyroid hormone physiology, molecular biology and gene regulation to decipher the internal signals that regulate the dramatic developmental event of metamorphosis in lampreys. Lamprey metamorphosis is analogous to the metamorphosis that transforms a fish-like tadpole into a frog. Lampreys are one of the most ancient living vertebrates (animals with a spinal column, including humans) and are a good model to study the evolution of developmental regulation and vertebrate ancestry. Interestingly, the start of lamprey metamorphosis coincides with a dramatic drop in thyroid hormone levels. This drop is opposite to the surge in thyroid hormone levels seen at the beginning of major developmental events in other vertebrates. The aims of this research program are to determine if this paradox of lamprey metamorphosis represents a fundamental difference in how thyroid hormones control development in lamprey (i.e. gene regulation) or more simply a difference in the physiological and cellular regulation of active hormone. Specifically this program will decipher the function and role in development of: a) systems in lamprey blood that transport thyroid hormones b) the enzymes that activate and inactivate the hormones in the cell and c) the receptors to which hormones bind to modulate gene activity. Lastly, we will also identify the lamrpey genes that are controlled by thyroid hormones and potentially drive metamorphosis. My research program will advance our understanding of the regulation of thyroid hormones and their role in the development of ancient vertebrates. Thyroid hormones are involved in many important biological processes in vertebrates including: development, growth, fat metabolism, temperature regulation, immune defense and reproduction. The unique nature of the lamprey thyroid system and its role in lamprey development may offer new insights into vertebrate thyroid physiology and dysfunction. Lastly, a better understanding of the factors that control lamprey development will provide novel opportunities to develop environmentally benign measures to control sea lamprey populations in the Great Lakes and reduce our reliance on current chemical treatments.