Evolution of Steroid Receptor-Hormone Interactions

类固醇受体-激素相互作用的演变

• 批准号: 6937294
• 负责人: JAMIE T BRIDGHAM
• 金额: $ 4.83万
• 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/6937294
• 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）：这项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的机械基础和进化动力学。将分子内分泌学，系统发育学和进化分析结合的跨学科方法将用于识别氨基酸变化，这些变化赋予糖皮质激素和矿物皮质激素受体（GR和MR）通过皮质醇和醛固酮的特异性激活，并通过醛固酮的过程来表征该过程。这些功能进化了。这将需要鉴定在GR和MR进化之前与家族不同的“茎”受体：来自hagfish的类固醇受体，由于其位置在脊椎动物谱系附近的位置，将被隔离，并在功能上分析，并在功能上分析，功能分析，并在功能上分析。来自另一个基部脊椎动物的那些海七lamp虫。然后将推断类固醇受体家族的系统发育，提供一个脚手架，以推断动力学并重建其数量，功能，序列和结构多样化的特定进化变化。最先进的统计技术将用于重建祖先受体的序列，MR和GR分化，该古代基因将合成，在细胞培养中表达，并在功能上表征以确定哪些功能是祖先是祖先并得出。然后将基于系统发育重建和现存的结构功能数据来生成有关新功能的机械基础的假设，这些假设将通过在祖先和现存受体中引入假定功能重要性的特异性突变来检验。预计这些部位为心脏和肾脏疾病的治疗干预提供了理想的目标。