Biomarkers for the two phase switches of mammalian hibernation

哺乳动物冬眠两个阶段转换的生物标志物

• 批准号: 7820965
• 负责人: SANDRA L MARTIN
• 金额: $ 2.46万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820965
• 关键词: Abbreviations; Animals; Arousal; Biochemical; Biological Markers; Biology; Body Temperature; Body Weight decreased; Brain; Brain Stem; Drug Delivery Systems; Ensure; Exhibits; Fatty acid glycerol esters; Foundations; Gel; Goals; Growth; Heart; Hibernation; Homeostasis; Hypothalamic structure; Ischemia; Life; Liquid Chromatography; Liver; Lung; Mammals; Mass Spectrum Analysis; Medicine; Metabolic; Molecular; Monitor; NMR Spectroscopy; Names; Nature; Organ; Phase; Phenotype; Plasma; Proteins; Proteomics; Protocols documentation; Reproduction; Resistance; Resources; Sampling; Science; Seasons; Spermophilus; Stroke; Telemetry; Testing; Tissue Banking; Tissue Banks; Tissue Extracts; Tissues; Trauma; Weight Gain; Work; animal tissue; depression; falls; metabolomics; natural hypothermia; protein metabolite; respiratory; success

Mammals that hibernate depress their metabolic, heart and respiratory rates, as well as their core body temperature (Tb) to enter a state called torpor. In hibernators such as ground squirrels, torpor is precisely controlled and fully reversible using only endogenous mechanisms, yet relatively little is known about the molecular events that underlie hibernation?s critical transitions. Understanding the biochemical aspects well enough to recapitulate them in a non-hibernator has profound implications for human health, offering an unprecedented opportunity to improve outcomes for victims of cardiac arrest, stroke, trauma, and hypothermia, as well as in organ transplant and routine surgery. Hibernation is an adaptive strategy for energy conservation that is exploited by many distantly related mammals; this broad phylogenetic distribution argues strongly that genetic capability underlying the phenotype is shared among mammals. Thus, we predict that an understanding of natural mammalian hibernation will lead to rational development of safe hypometabolic and protective strategies for human applications. Here we propose that hibernation comprises two biochemical switches: the first switch is a summer-to-winter switch that resets gene expression in a number of pathways leading to a protected phenotype. The second switch is a torporto- arousal switch that creates the heterothermic pattern characteristic to the hibernating phenotype and is responsible for reversible metabolic suppression. Markers associated with these two switches will be identified using proteomic and metabolomic techniques. The success of this work critically depends upon a carefully collected set of samples based upon the natural rhythms associated with the two switches. 21 sample groups from 13-lined ground squirrels will be analyzed, 9 for the summer-to-winter switch and 12 for the torpor-to-arousal switch. Initial focus will be on plasma, heart, lung, liver and brain, but other tissues will be collected to make a tissue bank of these valuable timepoints for additional studies and for use by the hibernation research community. Identification of these markers increases understanding of mammalian hibernation, and provides significant novel insights into natural mechanisms that achieve metabolic suppression and protection from ischemia/reperfusion injury in mammals. These markers offer an untapped source for discovery of new targets for therapeutic intervention in heart, lung and blood diseases in humans. Mammalian hibernation is a natural example of molecular and cellular adaptation to extreme environmental conditions; hibernators repeatedly cycle through periods of limited oxygen delivery and low body temperatures that would inevitably evoke lifethreatening cardiovascular and respiratory responses in humans. The understanding of the endogenous molecular mechanisms that permit these mammals to survive such physiological extremes offers untapped potential to discover drug targets and therapeutic interventions for the treatment and prevention of heart, blood, and lung diseases, as well as sleep and circadian rhythm disorders.

冬眠的哺乳动物会抑制它们的新陈代谢、心脏和 呼吸频率，以及他们的核心体温（Tb）进入一种称为麻木的状态。在 冬眠动物，如地松鼠，麻木是精确控制和完全可逆的，只使用 内源性机制，但相对知之甚少的分子事件， 冬眠？的关键转型。对生物化学方面的了解足以概括 它们在非冬眠动物中对人类健康有着深远的影响，提供了前所未有的 改善心脏骤停、中风、创伤和体温过低受害者预后的机会， 比如器官移植和常规手术冬眠是一种节能的适应性策略 被许多远亲哺乳动物利用;这种广泛的系统发育分布认为， 强烈地表明，表型背后的遗传能力在哺乳动物之间是共享的。因此，我们预测 对哺乳动物自然冬眠的理解将导致合理开发安全的 用于人类应用的低代谢和保护策略。这里我们提出冬眠 包括两个生化开关，第一个开关是重置基因的夏冬开关， 在许多途径中表达，导致受保护的表型。第二个开关是torporto- 唤醒开关，产生冬眠表型的异温模式特征， 负责可逆的代谢抑制。与这两个开关相关的标记将 使用蛋白质组学和代谢组学技术鉴定。这项工作的成功关键取决于 根据仔细收集的一组样本， 开关.将分析来自13个线地松鼠的21个样本组，其中9个用于夏季至冬季 开关和12个用于休眠-唤醒开关。最初的重点将是血浆、心脏、肺、肝脏和 大脑，但其他组织将被收集，使这些有价值的时间点的组织库， 更多的研究和使用的冬眠研究社区。识别这些标记 增加了对哺乳动物冬眠的了解，并为自然界提供了重要的新见解。 代谢抑制和保护缺血/再灌注损伤的机制 哺乳动物这些标记物为发现治疗性药物的新靶点提供了一个未开发的来源。 对人类心脏、肺和血液疾病的干预。哺乳动物的冬眠是一个自然的例子 分子和细胞适应极端环境条件的过程;冬眠动物反复循环 通过有限的氧气输送和低体温，这将不可避免地引起危及生命的 心血管和呼吸系统的反应。的理解 使这些哺乳动物能够在这种生理极端条件下生存的内源性分子机制 提供了尚未开发的潜力来发现药物靶点和治疗干预措施， 预防心脏、血液和肺部疾病，以及睡眠和昼夜节律紊乱。