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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

基本信息

批准号：
8022882
负责人：
SANDRA L MARTIN
金额：
$ 37.37万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8022882
关键词：
Animals Arousal Biochemical Biological Markers Biology Body Temperature Body Weight decreased Brain Brain Stem Cardiovascular system Characteristics Circadian Rhythm Sleep Disorders Communities Depressed mood Development Drug Delivery Systems Ensure Event Exhibits Fatty acid glycerol esters Foundations Gel Gene Expression Genetic Goals Growth Health Heart Heart Arrest Heart Diseases Hematological Disease Hibernation Homeostasis Human Hypothalamic structure Lead Life Liver Lung Lung diseases Mammals Medicine Mental Depression Metabolic Molecular Monitor Nature Operative Surgical Procedures Organ Organ Transplantation Outcome Oxygen Pathway interactions Pattern Phase Phenotype Phylogenetic Analysis Physiological 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 falls heart disease prevention improved insight metabolomics natural hypothermia novel protein metabolite respiratory response success

项目摘要

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新陈代谢、心脏和呼吸频率以及核心身体温度（Tb）进入一种称为休眠的状态。对于地松鼠等冬眠者来说，麻木正是仅使用内源机制进行控制和完全可逆，但人们对这一过程知之甚少冬眠关键转变背后的分子事件。很好地理解生化方面足以在非冬眠者中重现它们对人类健康具有深远的影响，提供了改善心脏骤停、中风、创伤和心脏骤停受害者的预后的前所未有的机会低温以及器官移植和常规手术。冬眠是一种适应性策略许多远亲哺乳动物都利用了能量守恒；这种广泛的系统发育分布强烈主张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有助于合理开发安全的冬眠方法人类应用的低代谢和保护策略。在这里我们建议冬眠包括两个生化开关：第一个开关是夏季到冬季的开关，可重置基因表达导致受保护表型的途径数量。第二个开关是从麻木到觉醒的开关创建冬眠表型特有的异温模式，并负责可逆代谢抑制。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。这项工作的成功关键取决于精心收集的样本集基于与两个开关相关的自然节律。 13 行地面的 21 个样本组将分析 9 只松鼠从夏季到冬季的转换，以及 12 只松鼠从麻木到觉醒的转换。最初的重点将放在血浆、心脏、肺、肝脏和大脑上，但也会收集其他组织来建立组织库这些宝贵的时间点可供进一步研究和冬眠研究界使用。这些标记的识别增加了对哺乳动物冬眠的了解，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颖见解哺乳动物的缺血/再灌注损伤。这些标记为发现新靶标提供了未开发的来源用于人类心脏、肺和血液疾病的治疗干预。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extensive use of torpor in 13-lined ground squirrels in the fall prior to cold exposure.

DOI：
10.1007/s00360-010-0484-8
发表时间：
2010-11
期刊：
Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology
影响因子：
0
作者：
Russell RL;O'Neill PH;Epperson LE;Martin SL
通讯作者：
Martin SL

Cytoskeletal regulation dominates temperature-sensitive proteomic changes of hibernation in forebrain of 13-lined ground squirrels.