Regulation and Function of Drosophila Nuclear Receptors

果蝇核受体的调控和功能

• 批准号: 7248577
• 负责人: CARL S. THUMMEL
• 金额: $ 32.45万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7248577
• 关键词: Address; Adolescent; Adult; Animals; Antibodies; Biological; Biological Metamorphosis; Biological Models; Caenorhabditis elegans; Cardiovascular Diseases; Characteristics; Cholesterol; Collection; Commit; Complex; Cycloheximide; Data; Development; Diabetes Mellitus; Drosophila genus; Drosophila melanogaster; Ecdysone; Ecdysterone; Functional disorder; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Growth; Homeostasis; Hormones; Human; Lipids; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Nuclear Receptor Gene; Nuclear Receptors; Obesity; Orthologous Gene; Pathway interactions; Pattern; Phase; Physiologic pulse; Pulse taking; RXR; Range; Receptor Signaling; Regulation; Research Personnel; Role; SXR receptor; Signal Pathway; Staging; Steroid Receptors; Steroids; Sterols; Testing; Vertebrates; ecdysteroid receptor; fly; follow-up; gain of function; gain of function mutation; human disease; in vivo; lipid metabolism; loss of function; member; mutant; programs; receptor; reproductive; response; steroid hormone; steroid hormone receptor; steroid metabolism; tool

DESCRIPTION (provided by applicant): The fruit fly Drosophila melanogaster has 18 nuclear receptor (NR) genes, significantly fewer than the 48 genes found in humans, spanning all vertebrate NR subclasses and encoding orthologs of key human receptors, including RXR (USP in flies), NGFI-B/NURR (DHR38), ERR (dERR), SXR (DHR96), and HNF4 (dHNF4). These characteristics of Drosophila NRs, combined with an extensive collection of genetic and genomic tools, establish the fly as an ideal model system for studying the molecular mechanisms of NR regulation and function. In this proposal, we focus on 2 major NR-regulated biological pathways: steroid-triggered maturation and lipid metabolism. Like vertebrates, Drosophila maturation is triggered by steroid hormones and their receptors, via complex transcriptional cascades that were identified and characterized in the fly. In contrast, no studies to date have addressed roles for Drosophila NRs in lipid metabolism. We will study the steroid regulation of a poorly understood transition that occurs during the last larval stage, when the animal commits to terminating its juvenile growth phase and initiating maturation via metamorphosis. We will identify genes regulated by alpha-ecdysone (E, the primary secreted steroid in Drosophila and the precursor to the active hormone 20-hydroxyecdysone, or 20E) and ask if these effects go through the DHR38 E receptor and its RXR partner, USP. We will determine if DHR38 and EcR function as partially redundant steroid receptors to initiate maturation. We will determine if dERR is transcriptionally controlled by 20E, examine its possible roles in initiating metamorphosis, and determine whether it controls lipid or sterol metabolism. We will follow up on the observation that DHR96 co-purifies with cholesterol and that DHR96 null mutants require cholesterol for their survival on minimal medium. Finally, we will characterize the expression and function of dHNF4 to define its roles in lipid metabolism and development. Metabolic profiling and microarrays will be used to gain a more complete understanding of the molecular mechanisms of dERR, DHR96, and dHNF4 function. Selected genes will be defined as direct regulatory targets. These studies will expand our understanding of NR signaling pathways with direct implications for how the orthologous NRs function in humans, as well as their contributions to critical human diseases associated with NR dysfunction, including cardiovascular disease, diabetes, and obesity.

描述（由申请人提供）：果蝇果蝇有 18 个核受体 (NR) 基因，明显少于人类中发现的 48 个基因，涵盖所有脊椎动物 NR 亚类并编码关键人类受体的直系同源物，包括 RXR（果蝇中的 USP）、NGFI-B/NURR (DHR38)、ERR (dERR)、SXR (DHR96) 和 HNF4 (dHNF4)。果蝇 NR 的这些特征，与广泛收集的遗传和基因组工具相结合，将果蝇建立为研究 NR 调节和功能分子机制的理想模型系统。在本提案中，我们重点关注 NR 调节的 2 个主要生物途径：类固醇触发的成熟和脂质代谢。与脊椎动物一样，果蝇的成熟是由类固醇激素及其受体通过在果蝇中鉴定和表征的复杂转录级联触发的。相比之下，迄今为止还没有研究探讨果蝇 NR 在脂质代谢中的作用。我们将研究类固醇对幼虫最后阶段发生的一个尚不清楚的转变的调节，此时动物致力于终止其幼年生长期并通过变态开始成熟。我们将鉴定受 α-蜕皮激素（E，果蝇中主要分泌的类固醇，也是活性激素 20-羟基蜕皮激素或 20E 的前体）调节的基因，并探究这些效应是否通过 DHR38 E 受体及其 RXR 伙伴 USP。我们将确定 DHR38 和 EcR 是否作为部分冗余的类固醇受体发挥作用来启动成熟。我们将确定 dERR 是否受 20E 转录控制，检查其在启动变态中的可能作用，并确定它是否控制脂质或甾醇代谢。我们将跟进 DHR96 与胆固醇共纯化以及 DHR96 无效突变体需要胆固醇才能在基本培养基上生存的观察结果。最后，我们将表征 dHNF4 的表达和功能，以确定其在脂质代谢和发育中的作用。代谢谱和微阵列将用于更全面地了解 dERR、DHR96 和 dHNF4 功能的分子机制。选定的基因将被定义为直接调控目标。这些研究将扩大我们对 NR 信号通路的理解，直接影响直系同源 NR 在人类中的功能，以及它们对与 NR 功能障碍相关的严重人类疾病的贡献，包括心血管疾病、糖尿病和肥胖。