Structure and Corresponding Receptors of Atypical Steroids in Sea Lamprey

七鳃鳗是脊椎动物中的一个关键群体，许多关于类固醇激素及其受体进化的假说都可以在其中得到验证。这项研究将开始通过测定海鳗(Petromyzon Marinus)中不寻常的类固醇的结构、受体和功能来检验这些假说。七鳃鳗是今天仅存的两类无颌鱼之一，其性腺在形态上与硬骨鱼相似，经历了与硬骨鱼相同的发育过程。然而，与硬骨鱼不同的是，七鳗鱼中没有类固醇与特定的生理功能有关。雄激素是一类通常与雄性生殖有关的类固醇，人们假设雄激素不是七鳃鳗体内的功能性激素，脊椎动物的雄激素受体是在无颌脊椎动物从有颌脊椎动物分化出来后才从祖先的雌激素受体进化而来的。然而，缺乏证据表明传统雄激素的功能及其相应受体的存在，可以用另一种假设来解释，即海鳗利用不寻常的雄激素和其他不寻常的性类固醇。这项拟议的研究将专注于寻找七鳃鳗中功能性类固醇，而不是典型的哺乳动物或硬骨鱼类固醇，而是那些在四环类固醇结构的碳15上增加了羟基的七鳗鱼。最终目标是确定含有15a-羟基的类固醇是否是海鳗体内的功能性性激素。特别是，这一假设将通过以下几个方面得到验证：(1)证实七鳃鳗性腺产生15a-羟化类固醇；(2)记录循环中15a-羟化类固醇对自然成熟的反应；(3)确定血浆中15a-羟化类固醇浓度如何随着七鳃鳗GnRH I和GnRH III的服药而变化；以及(4)描述假想的15a-羟化类固醇受体的结合特性。这项研究的预期结果也可能对海鳗的管理和保护产生重大影响，海鳗既是五大湖中的一种极具破坏性的有害物种，也是欧洲珍视的一种濒危物种。PI将通过吸收一名博士后研究员、一名美洲原住民研究生和几名本科生来促进教学和培训，并将包括来自经济贫困地区的高中生。

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.