Small Animal Metabolic Surgery (SAMS) Resource Core

描述(申请人提供)：肥胖造成的疾病负担是巨大的。肥胖非常普遍，并与60多种代谢、炎症、退行性、认知和肿瘤疾病有关。普遍有效的预防和治疗战略一直难以捉摸，世界各地的肥胖率继续上升。在目前的肥胖治疗方法中，各种形式的胃肠道减肥手术(GIWLS；减肥手术)已被证明是最有效和最持久的。最近的研究表明，这些手术主要通过影响体重的生理调节来发挥作用。它们影响新陈代谢功能的多个方面，在某些情况下，通过独立于体重减轻或食物摄入量减少的机制。这些特点使GIWLS成为检测代谢功能生理调节的一种有吸引力的方法。使用外科手术来探索生理机制是对其他研究这些调节途径的手段的补充，如药理学或遗传操作。结合外科、遗传学、营养学和药理学方法的力量，将有助于更好地理解正常和疾病状态下代谢生理学的细胞和分子机制。目前几乎所有可用的GIWLS程序的大鼠和小鼠模型的最近发展将有力地促进这一努力，但开发和维护这些模型的技术难度和高昂的成本是其使用的巨大障碍。这项提议的总体目标是建立一个小动物代谢手术(SAMS)核心资源，其服务将减少这些障碍，并促进在科学界更广泛地使用这些强大的模型。SAMS核心实验室提供了超过25种不同的GIWLS程序和相关手术的大鼠和小鼠外科模型。SAMS核心资源将通过以下方式促进它们的有效使用：(1)准备和分发来自这些模型的手术模型和标本，(2)培训研究人员准备和使用它们，(3)对手术操作的动物进行代谢和行为评估，(4)通过活体功能成像评估它们的生理，以及(5)建立和维护GIWLS对各种啮齿动物品系、基因操作动物和疾病模型的影响的数据库。由拟议的SAMS核心促进的GIWLS啮齿动物模型的更多使用将增加我们对代谢功能的细胞和分子调控的理解。它还将有助于确定这些手术的治疗益处的潜在机制。更好地了解这些机制将有助于确定针对肥胖引起或促进的数十种疾病的新的、更有效的疗法，并将促进开发更有效的方法来预防和治疗肥胖症本身。 公共卫生相关性：胃肠道减肥手术对体重和代谢功能的深刻生理影响使这些干预措施成为探索这些生理功能调节的宝贵工具。这些手术程序和相关植入装置在大鼠和小鼠身上的稳定、可靠和可重复的模型最近的发展极大地提高了它们对科学界的价值，但使用它们的技术和经济障碍是巨大的。这项建议旨在建立一个小动物代谢手术(SAMS)核心资源基金，以促进在肥胖和代谢紊乱影响的许多学科工作的研究人员有效地使用这些啮齿动物模型。根据核心用户的需求，SAMS核心将准备供核心用户研究的动物模型，培训研究人员在他们自己的实验室内准备他们的模型，并在体内使用代谢和行为评估以及几种功能成像模式来表征各种本地、转基因或携带疾病的啮齿动物模型的手术效果。

DESCRIPTION (provided by applicant): The burden of disease attributable to obesity is enormous. Obesity is highly prevalent and associated with more than 60 metabolic, inflammatory, degenerative, cognitive, and neoplastic disorders. Broadly effective preventive and therapeutic strategies have been elusive, and rates of obesity continue to increase in all parts of the world. Among the current therapies for obesity, various forms of gastrointestinal weight loss surgery (GIWLS; bariatric surgery) have proven to be far and away the most effective and durable. Recent studies have demonstrated that these operations work primarily by affecting the physiological regulation of body weight. They affect multiple aspects of metabolic function, in some cases through mechanisms independent of weight loss or diminished food intake. These characteristics make use of GIWLS an attractive approach to examining physiological regulation of metabolic function. Using surgery to probe physiological mechanism is complementary to other means of studying these regulatory pathways, such as pharmacological or genetic manipulation. Combining the power of surgical, genetic, nutritional and pharmacological approaches will facilitate greater understanding of the cellular and molecular mechanisms underlying metabolic physiology in normal and disease states. The recent development of rat and mouse models of nearly all of the currently available GIWLS procedures will strongly facilitate this effort, but the technical difficulty and high cost of developing and maintaining these models is a formidable barrier to their use. The overall goal of this proposal is to establish a Small Animal Metabolic Surgery (SAMS) Core Resource whose services would reduce these barriers and facilitate use of these powerful models more broadly within the scientific community. More than 25 distinct rat and mouse surgical models of GIWLS procedures and related operations are available within the SAMS Core laboratory. The SAMS Core Resource will facilitate their effective use by (1) preparing and distributing surgical models and specimens from these models, (2) training investigators in their preparation and use, (3) performing metabolic and behavioral assessment of surgically manipulated animals, (4) assessing their physiology by in vivo functional imaging, and (5) establishing and maintaining a database of the effects of GIWLS in various rodent strains, genetically manipulated animals and disease models. The greater use of rodent models of GIWLS facilitated by the proposed SAMS Core will increase our understanding of the cellular and molecular regulation of metabolic function. It will also help to identify the mechanisms underlying the therapeutic benefits of these operations. Greater understanding of these mechanisms will contribute to the identification of new, more effective therapies for the several dozen diseases caused or promoted by obesity and will facilitate the development of more effective means of preventing and treating obesity itself. PUBLIC HEALTH RELEVANCE: The profound physiological effects of gastrointestinal weight loss surgery on body weight and metabolic function make these interventions valuable tools for probing the regulation of these physiological functions. The recent development of stable, reliable and reproducible models of these surgical procedures and related implantable devices in rats and mice strongly enhances their value to the scientific community, but the technical and economic barriers to their use are formidable. This proposal aims to establish a Small Animal Metabolic Surgery (SAMS) Core Resource Facility to facilitate the effective use of these rodent models by investigators working in the many disciplines affected by obesity and metabolic disorders. In response to the needs of Core users, the SAMS Core will prepare animal models for study by Core users, train investigators to prepare their models within their own laboratories, and use metabolic and behavioral assessment and several functional imaging modalities in vivo to characterize the effects of surgery in a variety of native, genetically modified or disease-bearing rodent models.