CAREER: Molecular Evolution of Steroid Hormone Receptor Function And Interactions

职业：类固醇激素受体功能和相互作用的分子进化

• 批准号: 0546906
• 负责人: Joseph Thornton
• 金额: $ 91.17万
• 依托单位: University of Oregon Eugene
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0546906&HistoricalAwards=false
• 关键词: CAREER; Molecular; Evolution; Steroid; Hormone

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.

类固醇激素受体功能和相互作用的分子进化。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而实现的。 例如，性腺或肾上腺产生的类固醇激素，如雌激素、睾丸激素和皮质醇，调节发育、生殖、行为和无数其他过程。 每种激素通过与靶细胞中的特定受体蛋白结合而产生一系列独特的效应;然后，与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重要的生物学意义，但了解紧密的分子伙伴关系如何演变的工作很少。该职业计划将分子相互作用演变的研究与教育和推广活动相结合，以加强对进化，内分泌学的理解，并将科学知识应用于公共政策。 在该项目的研究部分，类固醇激素及其受体将被用作模型系统，其目标是重建激素和受体之间特定相互作用的进化机制。首先，研究人员将从几个目标物种中分离和表征受体，由于它们在生命树中的位置，将提供有关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、结构和被新激素激活的能力方面多样化的动态。然后，研究人员将通过“复活”祖先受体基因并在实验室中研究它们的功能来测试关于受体如何进化出新功能的假设。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活的祖先基因并确定其对受体与各种激素相互作用的影响来导致受体进化新功能。 本建议的教育和外联部分侧重于科学与现实世界政策问题的接口。将开发一门新的课程，通过教导年轻科学家批判性地思考科学在政策过程中的部署方式，为他们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-将被用作扩展案例研究。一个大型的进化生物学本科课程将被修订，以更好地纳入进化知识的应用影响。 最后，首席研究员将担任两个非政府组织的临时科学顾问，这些组织直接与环境内分泌干扰和人类健康方面的大型赞助商合作。