Development and use of a novel, tractable rodent model for studies of hibernation metabolism

 描述(申请人提供)：冬眠的哺乳动物，包括熊、蝙蝠、啮齿动物和至少一种灵长类动物，在冬眠前经历一段时间的快速体重增加，这使它们能够积累存活长达6个月的冬眠所需的脂肪储备。在冬眠期间，这些动物既不吃也不喝，但在使用储存的脂肪作为主要燃料来源的同时，显著抑制了它的代谢率。对冬眠的机械论理解可能会对人类医学产生重要影响。在冬眠者身上发现的一些适应性代谢状态，如冬眠前的胰岛素抵抗和脂肪堆积，与人类出现的适应不良代谢综合征相似，而在人类中创造类似冬眠的状态的能力可能会对紧急药物、手术或器官储存产生重大影响。然而，冬眠表型背后的机制在很大程度上仍然不清楚，之前的研究努力由于缺乏易于处理的实验模型而受到限制。该项目将建立北美小型冬眠动物草甸跳跃老鼠(Zapus Hudsonius)作为冬眠的实验室模型。与目前的模式不同，Zapus的世代时间很短，可以利用光周期和温度诱导它冬眠，而不受外界季节的影响。这个项目的总体目标是1)对Zapus基因组进行测序和注释，并将Zapus的基因组与一个密切相关的非冬眠者的基因组进行比较；2)建立一个强大的繁殖群体，改进诱导肥胖和冬眠所需的条件；以及3)比较夏季活跃、肥胖和冬眠状态下全身和组织特有的细胞代谢，重点是糖代谢的调节。该项目旨在将草地跳跃老鼠建立为一种易驯服的冬眠遗传模型。拟议的代谢特征将通过提供关于冬眠新陈代谢的第一个全面视图来推进冬眠领域。这项工作的长期目标是为全面研究冬眠表型的机制奠定基础，这可能对人类健康具有重要的应用。

 DESCRIPTION (provided by applicant): Hibernating mammals, including bears, bats, rodents, and at least one primate, undergo a period of rapid pre-hibernation weight gain, which allows them to build the fat reserves needed to survive up to 6 months of hibernation. During hibernation, the animals neither eat nor drink, but significantly suppresses its metabolic rate while using stored fat as the primary fuel source. A mechanistic understanding of hibernation could have an important impact on human medicine. Some of the adaptive metabolic states found in hibernators, such as pre-hibernation insulin resistance and fat accumulation, are similar to the maladaptive metabolic syndrome seen in humans, and an ability to create a hibernation-like state in humans could have a significant impact on emergency medicine, surgery or organ storage. However, the mechanisms underlying hibernation phenotypes remain largely unknown, and previous research efforts have been limited by the lack of tractable experimental models. This project will establish the meadow jumping mouse (Zapus hudsonius), a small North American hibernator, as a laboratory model of hibernation. Unlike current models, Zapus has a short generation time and it can be induced to hibernate using photoperiod and temperature regardless of outside season. The overall goals of this project are 1) to sequence and annotate the Zapus genome, and to compare the genome of Zapus with that of a closely related non-hibernator; 2) to establish a robust breeding colony and refine the conditions required to induce obesity and hibernation; and 3) to compare whole body and tissue-specific cellular metabolism in the summer-active, obese, and hibernating states, with a focus on regulation of glucose metabolism. This project is designed to establish the meadow jumping mouse as a tractable, genetic model of hibernation. The proposed metabolic characterization will advance the hibernation field by providing the first comprehensive view of hibernation metabolism. The long-term goal of this work is to lay the foundation for comprehensive study of the mechanisms of hibernation phenotypes, which may have important application to human health.