Structure and Corresponding Receptors of Atypical Steroids in Sea Lamprey

七鳃鳗是脊椎动物中一个重要的群体，许多关于类固醇激素及其受体进化的假设都可以在其中得到检验。本研究将通过测定海七鳃鳗（Petromyzon marinus）中不寻常类固醇的结构、受体和功能来开始测试这些假设。七鳃鳗是现存的两种无颌鱼类中的一种，它们的性腺在形态上与硬骨鱼（硬骨鱼）相似，并且经历了相同的发育过程。然而，与硬骨鱼不同的是，七鳃鳗体内没有类固醇与特定的生理功能有关。有一种假说认为，雄激素（一种通常与雄性生殖有关的类固醇）在七鳃鳗中不是功能性激素，而脊椎动物的雄激素受体是在无颌脊椎动物与有颌脊椎动物分化之后才从祖先的雌激素受体进化而来的。然而，缺乏关于常规雄激素功能及其相应受体存在的证据，可以用另一种假设来解释，即海七鳃鳗利用不寻常的雄激素和其他不寻常形式的性类固醇。这项研究将把重点放在寻找七鳃鳗的功能性类固醇上，这些类固醇在四环类固醇结构的碳15上有一个额外的羟基，而不是典型的哺乳动物或硬骨鱼类固醇。最终目的是确定具有15a-羟基的类固醇是否是海七鳃鳗的功能性激素。具体来说，这一假设将通过：(1)证实海七鳃鳗性腺产生15a-羟化类固醇；(2)记录15a-羟基化类固醇在自然成熟过程中的变化；(3)确定15a-羟化类固醇的血浆浓度如何随着七鳃鳗GnRH I和GnRH III的使用而变化，这两种物质已知会刺激成熟；(4)表征15a-羟基化类固醇的假设受体的结合特性。这项研究的预期结果也可能对海洋七鳃鳗的管理和保护产生重大影响，七鳃鳗既是五大湖中一种极具破坏性的害虫，也是欧洲一种被视为美味佳肴的濒危物种。该项目将促进教学和培训，包括一名博士后、一名印第安人研究生、几名本科生，以及来自经济落后地区的高中生。

Lampreys represent a key group of vertebrate animals in which many hypotheses concerning the evolution of steroid hormones and their receptors can be tested. This study will begin to test these hypotheses through determination of the structures, receptors, and functionality of unusual steroids in the sea lamprey (Petromyzon marinus). The gonads of the lamprey, one of only two groups of jawless fishes still alive today, are morphologically similar and undergo the same developmental processes as those of teleost (bony) fish. However, unlike teleosts, no steroids in lamprey have been linked to specific physiological functions. It has been hypothesized that androgens, a class of steroids normally associated with male reproduction, are not functional hormones in lampreys, and that vertebrate androgen receptors evolved from an ancestral estrogen receptor only after jawless vertebrates diverged from jawed vertebrates. However, the lack of evidence for the functionality of conventional androgens and the presence of their corresponding receptors may be explained by the alternative hypothesis that sea lampreys utilize unusual androgens and other unusual forms of sex steroids. This proposed study would focus the search for functional sex steroids in lamprey on those with an additional hydroxyl group on carbon 15 of the four-ring steroid structure, and not on typical mammalian or teleost steroids. The ultimate goal is to determine whether steroids with a 15a-hydroxyl group are functional sex hormones in the sea lamprey. In particular, this hypothesis will be tested by: (1) Confirming that sea lamprey gonads produce 15a-hydroxylated steroids; (2) Documenting changes in circulatory 15a-hydroxylated steroids in response to natural maturation; (3) Determining how plasma concentrations of 15a-hydroxylated steroids change in response to administration of lamprey GnRH I and GnRH III, which are known to stimulate maturation; and (4) Characterizing the binding properties of hypothesized receptors for 15a-hydroxylated steroids. Anticipated results from this study may also have significant implications in management and conservation of the sea lamprey, which is both a highly destructive pest species in the Great Lakes and an endangered species prized as a delicacy in Europe. The PI will promote teaching and training by involving a post-doctoral fellow, a Native American graduate student, several undergraduate students, and will include high-school students from an economically disadvantaged region.