CAREER: Molecular Evolution of Steroid Hormone Receptor Function And Interactions

职业生涯：类固醇激素受体功能和相互作用的分子进化俄勒冈大学约瑟夫·W·桑顿实际上，活细胞所做的一切都是通过分子之间非常特殊的相互作用来实现的。例如，性腺或肾上腺产生的类固醇激素--如雌激素、睾酮和皮质醇--调节发育、生殖、行为和无数其他过程。每种激素都通过与靶细胞中的特定受体蛋白结合来产生一系列独特的效应；然后，激素结合的受体进入细胞核，与一组特定的DNA序列结合，并激活附近基因的表达。尽管像这样的特定相互作用具有巨大的生物学重要性，但对于了解紧密的分子伙伴关系是如何演变的工作却很少。这份职业规划将分子相互作用的进化研究与教育和外联活动结合在一起，这些活动加强了对进化、内分泌学和公共政策中科学知识的运用的理解。在该项目的研究部分，类固醇激素及其受体将被用作一个模型系统，目标是重建激素和受体之间特定相互作用进化的进化机制。首先，研究人员将从几个目标物种中分离和鉴定受体，因为它们在生命树上的位置，将提供关于受体基因家族多样化的关键信息。系统发育技术将被用来推断该家族在数量、分子序列、结构以及被新激素激活的能力方面的多样性。然后，研究人员将通过“复活”祖先的受体基因并在实验室研究它们的功能，来测试受体如何进化出新的功能的假设。最后，将进行实验，以确定DNA水平的变化如何通过将历史突变重新引入复兴的祖先基因来导致受体进化新功能，并确定它们对受体与各种激素相互作用的影响。该提案的教育和宣传部分侧重于科学与现实世界政策问题之间的联系。将开发一门新课程，通过教年轻科学家批判性地思考科学在政策过程中的运用方式，为参与社会决策做好准备；环境内分泌干扰物--干扰人体类固醇激素的污染物--将被用作扩展的案例研究。进化生物学的一门大型本科课程将被修订，以更好地纳入进化知识的应用含义。最后，首席研究员将担任两个非政府组织的临时科学顾问，这两个组织直接与大量支持者合作，研究环境内分泌干扰和人类健康。

CAREER: Molecular Evolution of Steroid Hormone Receptor Functions and InteractionsJoseph W. ThorntonUniversity of OregonVirtually everything that living cells do is made possible by very specific interactions between molecules. For example, steroid hormones produced in the gonads or adrenal gland-such as estrogen, testosterone, and cortisol-regulate development, reproduction, behavior, and countless other processes. Each hormone produces a unique suite of effects by binding to a specific receptor protein in target cells; the hormone-bound receptor then enters the nucleus, binds to a specific set of DNA sequences, and activates the expression of nearby genes. Despite the great biological importance of specific interactions like this, there has been very little work to understand how tight molecular partnerships evolve.This career plan integrates research on the evolution of molecular interactions with education and outreach activities that strengthen understanding of evolution, endocrinology, and the deployment of scientific knowledge in public policy. In the project's research component, steroid hormones and their receptors will be used as a model system, with the goal of reconstructing the evolutionary mechanisms by which the specific interactions between hormones and receptors evolved. First, the investigators will isolate and characterize receptors from several target species that, because of their position in the tree of life, will provide crucial information about the diversification of the receptor gene family. Phylogenetic techniques will be used to infer the dynamics by which the family diversified in number, molecular sequence, structure, and the ability to be activated by new hormones. The investigators will then test hypotheses about how receptors evolved novel functions by "resurrecting" ancestral receptor genes and studying their functions in the laboratory. Finally, experiments will be performed to determine how changes at the DNA level caused receptors to evolve new functions by re-introducing historical mutations into resurrected ancestral genes and determining their effects on the receptors' interactions with various hormones. The education and outreach components of this proposal are focused on the interface of science with real-world policy issues. A new course will be developed, which prepares young scientists to participate in societal decision-making by teaching them to think critically about the ways that science is deployed in the policy process; environmental endocrine disrupters-pollutants that interfere with the body's steroid hormones - will be used as an extended case study. A large undergraduate course in Evolutionary Biology will be revised to better incorporate the applied implications of evolutionary knowledge. Finally, the principal investigator will serve as an occasional science advisor to two nongovernmental organizations that work directly with large constituencies on environmental endocrine disruption and human health.