Evolution of Steroid Receptor-Hormone Interactions

类固醇受体-激素相互作用的演变

• 批准号: 7095141
• 负责人: JAMIE T BRIDGHAM
• 金额: $ 5.04万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095141
• 关键词: aldosterone; animal genetic material tag; animal tissue; binding sites; biochemical evolution; corticosteroid receptors; cortisol; gene expression; hormone regulation /control mechanism; intermolecular interaction; ligands; model design /development; nucleic acid sequence; physical model; postdoctoral investigator; protein structure function; receptor binding; receptor expression; site directed mutagenesis; statistics /biometry; tissue /cell culture

DESCRIPTION (provided by applicant): The goal of this research is to reveal the mechanistic basis and evolutionary dynamics by which specific functional interactions between adrenal steroids and their receptors evolved. An interdisciplinary approach combining molecular endocrinology, phylogenetics, and evolutionary analysis will be used to identify the amino acid changes that conferred on the glucocorticoid and mineralocorticoid receptors (GR and MR) their specific activation by cortisol and aldosterone and to characterize the dynamics of the process by which these functions evolved. This will entail identification of "stem" receptors that diverged from the family before the GR and MR evolved: steroid receptors from the hagfish, a key phylogentic species due to its position near the base of the vertebrate lineage, will be isolated and functionally analyzed, as will those from another basal vertebrate, the sea lamprey. The steroid receptor family phylogeny will then be inferred, providing a scaffold on which to infer the dynamics and reconstruct the specific evolutionary changes by which they have diversified in number, function, sequence, and structure. State-of-the-art statistical techniques will be used to reconstruct the sequence of the ancestral receptor from which the MR and GR diverged, and this ancient gene will be synthesized, expressed in cell culture, and functionally characterized to determine which functions are ancestral and derived. Hypotheses about the mechanistic basis for the emergence of novel functions will then be generated based on the phylogenetic reconstruction and extant structure-function data, and these hypotheses will be tested by introducing specific mutations of putative functional importance into both ancestral and extant receptors. These sites are predicted to provide ideal targets for therapeutic interventions for heart and kidney disease.

描述（由申请人提供）：本研究的目的是揭示肾上腺类固醇及其受体之间特定功能相互作用进化的机制基础和进化动力学。结合分子内分泌学、系统发育学和进化分析的跨学科方法将用于确定糖皮质激素和矿皮质激素受体（GR和MR）被皮质醇和醛固酮特异性激活的氨基酸变化，并描述这些功能进化过程的动力学特征。这将需要识别在GR和MR进化之前从家族中分离出来的“茎”受体：盲鳗是一个关键的系统发育物种，因为它位于脊椎动物谱系的底部，将被分离出来并进行功能分析，另一种基础脊椎动物——海七鳃鳗的类固醇受体也将被分离出来。然后，类固醇受体家族的系统发育将被推断出来，为推断动态和重建它们在数量、功能、序列和结构上多样化的特定进化变化提供一个框架。最先进的统计技术将用于重建MR和GR分化的祖先受体序列，并且该古老基因将被合成，在细胞培养中表达，并进行功能表征以确定哪些功能是祖先和衍生的。关于新功能出现的机制基础的假设将基于系统发育重建和现存的结构-功能数据产生，这些假设将通过将假定的功能重要性的特定突变引入祖先和现存受体来验证。预计这些位点将为心脏和肾脏疾病的治疗干预提供理想的靶点。

项目成果

An epistatic ratchet constrains the direction of glucocorticoid receptor evolution.

• DOI: 10.1038/nature08249
• 发表时间: 2009-09-24
• 期刊: Nature
• 影响因子: 64.8
• 作者: Bridgham JT;Ortlund EA;Thornton JW
• 通讯作者: Thornton JW