Functional Genomics of Mammalian Hibernation

哺乳动物冬眠的功能基因组学

• 批准号: 9333678
• 负责人: Thomas S Kilduff
• 金额: $ 26.8万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333678
• 关键词: Aging; Animals; Apnea; Arousal; Behavioral; Biochemical; Bioinformatics; Biology; Body Temperature; Brain region; Cerebral cortex; Cerebrum; Chicago; Circadian Rhythms; Collaborations; Contractor; Data; Databases; Disuse Atrophy; Drops; Endocrine; Ensure; Food; Gene Expression; Genome; Goals; Health; Heart Rate; Hibernation; Homeostasis; Hour; Human; Hypothalamic structure; Individual; International; Ischemia; Laboratories; Liver; Medical center; Memory; Memory Loss; Metabolic; Metabolism; Mining; Molecular; Muscle; Muscular Atrophy; Neurobiology; Organ; Organ Preservation; Organism; Oxygen; Pediatric Hospitals; Peripheral; Phase; Physiological Processes; Physiology; Pontine structure; Preparation; Proteomics; Publishing; Regulation; Reproduction; Respiration; Role; Sampling; Seasons; Series; Shotgun Sequencing; Sleep; Spermophilus; Stroke; Stroke prevention; Synapses; System; Testing; Time; Tissue Banks; Tissue Sample; Tissues; United States National Library of Medicine; basal forebrain; base; body system; cDNA Library; deep sequencing; experience; falls; functional genomics; genome annotation; genome sequencing; insight; prevent; scaffold; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Mammalian hibernation is an integrative organismal adaptation involving a coordinated orchestration of systems physiology that results in a seasonally expressed change in behavioral state. As body temperature declines from euthermic values of 36-38°C to 2°C or lower in the ground squirrel, heart rate drops from 200- 300 beats/min to 7-10 beats/min, respiration rates fall from 100-150 breaths/min to 1-2 breaths/min, and metabolism declines to 1/30 to 1/100 of euthermic values. The mechanisms that underlie the entrance into, and arousal from, hibernation are poorly understood. However, the molecular, neurobiological, and endocrine adaptations underlying these dramatic arousal state changes are likely to have significance for human health in understanding metabolic homeostasis and aging, as well as for strategies to enhance organ preservation. Transcriptomic and proteomic studies have begun to describe the molecular landscape that underlies these changes in arousal state. To date, published studies have primarily focused on one organ system at a time, with little effort at integration across systems. In this proposal, we will exploit a bank of 12 dissected brain regions and 10 peripheral tissues collected from the golden-mantled ground squirrel (Callospermophilus lateralis) at 12 time points across the 5 major phases of the hibernation cycle to create a public database of transcriptomic information from the same individuals. In Aim 1, genome sequencing and de novo assembly of the C. lateralis genome will be conducted by a contractor who has previously assembled the genome of the 13- lined ground squirrel; the resultant genome will be annotated in collaboration with colleagues at the National Library of Medicine. These efforts will provide the necessary scaffold to enable Aim 2, whose goal is to conduct RNAseq analyses of multiple brain regions sampled across the hibernation cycle and to establish a public database of transcriptomic information. Our studies will initially focus on basal forebrain, hypothalamus, pons, and cerebral cortex because of their distinct roles in arousal state regulation. This RNAseq data will enrich the genome annotation conducted in Aim 1. The RNAseq data will be visualized and made available for mining through a publicly available database similar to CircaDB (http://circadb.hogeneschlab.org), a gene expression database widely used in circadian biology, that we will create in Aim 2b. The database will be extensible, enabling addition of transcriptomic and proteomic data from other brain regions and peripheral organs by our group as well as others. Collectively, this information will fuel hypothesis testing and organism-wide interrogation of the molecular bases of the dynamic changes in physiology that occur across the hibernation cycle and may provide insights into the adaptations that enable metabolic suppression and those that prevent hibernators from experiencing stroke, apnea, muscle atrophy and memory loss.

项目概要 哺乳动物冬眠是一种综合的有机适应，涉及协调编排 导致行为状态季节性变化的系统生理学。随着体温 地松鼠的体温从 36-38°C 降至 2°C 或更低，心率从 200- 300次/分钟降至7-10次/分钟，呼吸频率从100-150次/分钟降至1-2次/分钟，并且 新陈代谢下降至常温值的 1/30 至 1/100。进入的机制， 人们对冬眠的唤醒知之甚少。然而，分子、神经生物学和内分泌 这些戏剧性的唤醒状态变化背后的适应可能对人类健康具有重要意义 了解代谢稳态和衰老，以及增强器官保存的策略。 转录组学和蛋白质组学研究已经开始描述这些基础的分子景观 觉醒状态的变化。迄今为止，已发表的研究主要集中在一次一个器官系统上， 在跨系统集成方面花费很少的精力。在这个提案中，我们将利用一组 12 个解剖大脑 从金毛地松鼠（Callospermophilus）收集的区域和 10 个外周组织 oralis）在冬眠周期的 5 个主要阶段的 12 个时间点创建一个公共数据库 来自同一个体的转录组信息。在目标 1 中，基因组测序和从头组装 C. Lateralis 基因组将由承包商进行，该承包商之前已经组装了 13- 内衬地松鼠；由此产生的基因组将与国家实验室的同事合作进行注释 医学图书馆。这些努力将为实现目标 2 提供必要的基础，其目标是开展 RNAseq 分析整个冬眠周期中多个大脑区域的样本，并建立一个公共模型 转录组信息数据库。我们的研究最初将集中于基底前脑、下丘脑、脑桥、 和大脑皮层，因为它们在唤醒状态调节中发挥着独特的作用。该 RNAseq 数据将丰富 目标 1 中进行基因组注释。RNAseq 数据将可视化并可用于挖掘 通过类似于 CircaDB (http://circadb.hogeneschlab.org) 的公开数据库，基因表达 我们将在 Aim 2b 中创建广泛用于昼夜节律生物学的数据库。数据库将是可扩展的， 通过我们的研究，可以添加来自其他大脑区域和外周器官的转录组和蛋白质组数据 团体以及其他团体。总的来说，这些信息将推动假设检验和整个组织的发展。 探究冬眠期间发生的生理动态变化的分子基础 循环，并可能提供对能够抑制代谢和阻止代谢的适应的见解 冬眠者不会出现中风、呼吸暂停、肌肉萎缩和记忆丧失。