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: 7426147
• 负责人: SANDRA L MARTIN
• 金额: $ 37.68万
• 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/7426147
• 关键词: Animals; Arousal; Biochemical; Biological Markers; Biology; Blood; Body Temperature; Body Weight decreased; Brain; Brain Stem; Cardiovascular system; Characteristics; Circadian Rhythm Sleep Disorders; Communities; Condition; Depressed mood; Depth; 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; Life; Liver; Lung; Lung diseases; Mammals; Medicine; Mental Depression; Metabolic; Molecular; Monitor; Nature; Numbers; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome; Oxygen; Pathway interactions; Pattern; Phase; Phenotype; Phylogenetic Analysis; Physiological; Plasma; Prevention; Proteins; Proteomics; Protocols documentation; Range; Rate; 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; base; falls; improved; insight; metabolomics; natural hypothermia; novel; protein metabolite; respiratory; response; success

DESCRIPTION (provided by applicant): 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. 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 life-threatening 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.

描述（由申请人提供）：冬眠的哺乳动物降低其代谢率、心率和呼吸率，以及其核心体温（Tb），进入一种称为麻痹的状态。在地松鼠等冬眠动物中，冬眠是精确控制的，并且完全可逆，只使用内源性机制，但对冬眠关键转变的分子事件知之甚少。充分了解生物化学方面，使其在非冬眠动物中重现，对人类健康具有深远的意义，为改善心脏骤停、中风、创伤和体温过低受害者的预后以及器官移植和常规手术提供了前所未有的机会。冬眠是一种适应性的能源节约策略，被许多远亲哺乳动物利用;这种广泛的系统发育分布有力地证明了哺乳动物之间共享表型的遗传能力。因此，我们预测，自然哺乳动物冬眠的理解将导致合理的发展安全的代谢和保护策略，为人类的应用。在这里，我们提出，冬眠包括两个生化开关：第一个开关是一个夏季到冬季的开关，重置基因表达的一些途径，导致一个受保护的表型。第二个开关是休眠-觉醒开关，它产生冬眠表型特有的异温模式，并负责可逆的代谢抑制。将使用蛋白质组学和代谢组学技术鉴定与这两个开关相关的标记物。这项工作的成功关键取决于一组仔细收集的样本，这些样本是基于与两个开关相关的自然节律。将分析来自13只地松鼠的21个样本组，9个用于夏季到冬季的转换，12个用于休眠到觉醒的转换。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，使这些宝贵的时间点的组织库，为进一步的研究和冬眠研究界使用。这些标志物的鉴定增加了对哺乳动物冬眠的理解，并为哺乳动物中实现代谢抑制和保护免受缺血/再灌注损伤的自然机制提供了重要的新见解。这些标记物为发现人类心脏、肺和血液疾病治疗干预的新靶点提供了一个尚未开发的来源。哺乳动物冬眠是分子和细胞适应极端环境条件的自然例子;冬眠者反复循环有限的氧气输送和低体温，这将不可避免地引起危及人类生命的心血管和呼吸反应。对允许这些哺乳动物在这种生理极端条件下生存的内源性分子机制的理解提供了未开发的潜力，以发现用于治疗和预防心脏、血液和肺部疾病以及睡眠和昼夜节律紊乱的药物靶点和治疗干预。