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: 7586799
• 负责人: SANDRA L MARTIN
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586799
• 关键词: Abbreviations; Animals; Arousal; Biochemical; Biological Markers; Biology; Body Temperature; Body Weight decreased; Brain; Brain Stem; Characteristics; Communities; Development; Drug Delivery Systems; Ensure; Event; Exhibits; Fatty acid glycerol esters; Foundations; Gel; Gene Expression; Genetic; Goals; Growth; Health; Heart; Heart Arrest; Hematological Disease; Hibernation; Homeostasis; Human; Hypothalamic structure; Lead; Liquid Chromatography; Liver; Lung; Mammals; Mass Spectrum Analysis; Medicine; Metabolic; Molecular; Monitor; NMR Spectroscopy; Names; Nature; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome; Pathway interactions; Pattern; Phase; Phenotype; Phylogenetic Analysis; Plasma; Proteins; Proteomics; Protocols documentation; Reperfusion Injury; Reproduction; Research; Resistance; Resources; Sampling; Science; Seasons; Source; Spermophilus; Stroke; Techniques; Telemetry; Testing; Therapeutic Intervention; Tissue Banking; Tissue Banks; Tissue Extracts; Tissues; Trauma; Weight Gain; Work; animal tissue; base; depressed; depression; falls; improved; insight; metabolomics; natural hypothermia; novel; 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 torpor-to-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.

冬眠的哺乳动物会降低它们的新陈代谢、心跳和呼吸频率，以及它们的核心身体 温度（Tb）进入一种称为休眠的状态。在地松鼠这样的冬眠动物中， 控制和完全可逆的，只使用内源性机制，但相对知之甚少， 冬眠关键转变的分子事件了解生物化学方面的知识 足以在非冬眠动物中重现它们对人类健康有着深远的影响， 前所未有的机会，改善心脏骤停，中风，创伤和 低温，以及器官移植和常规手术。冬眠是一种适应性策略， 被许多远亲哺乳动物利用的能量保存;这种广泛的系统发育分布 强烈认为，遗传能力的表型是共享的哺乳动物。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。在这里，我们提出，冬眠包括 两个生化开关：第一个开关是从夏季到冬季的开关，它重置了基因表达， 导致受保护表型的途径的数量。第二个开关是一个从休眠到唤醒的开关， 创造了异温模式的特点，冬眠表型，并负责可逆的 代谢抑制与这两个开关相关的标志物将使用蛋白质组学和免疫组织化学鉴定。 代谢组学技术这项工作的成功关键取决于一组精心收集的样本 基于与两个开关相关联的自然节律。13线地面21个样本组 将对松鼠进行分析，其中9只用于夏季到冬季的转换，12只用于休眠到觉醒的转换。初始 重点将放在血浆，心脏，肺，肝脏和大脑，但其他组织将被收集，使组织库的 这些宝贵的时间点进行额外的研究和使用的冬眠研究社区。 这些标记的鉴定增加了对哺乳动物冬眠的理解，并提供了重要的信息。 对实现代谢抑制和保护的自然机制的新见解 哺乳动物缺血/再灌注损伤。这些标记物为发现新靶点提供了一个尚未开发的来源 用于人类心脏、肺和血液疾病的治疗干预。