Better mouse models of disease: Humanizing experimental atherosclerosis

描述(由申请人提供)：小鼠已经成功地成为生物医学研究中选择的活体实验模型系统。然而，老鼠模型有明显的局限性。文献中充斥着在老鼠身上奏效但在人类身上失败的治疗方法。此外，小鼠往往不能很好地模拟所模拟的人类疾病，动脉粥样硬化就是最好的例子。与人类相比，老鼠对动脉粥样硬化的抵抗力很强。在某种程度上，这被认为是由于不同物种之间脂蛋白代谢的根本差异。因此，现有的小鼠模型是基于脂蛋白代谢的饮食或遗传扰动；所有这些模型都有缺陷。虽然小鼠模型提供了对发病机制的重要见解，但现有模型存在的基本生物学和实际问题阻碍了将小鼠研究得出的原理转化为人类疾病。与其他难以建模的疾病一样，这被推定是由于物种之间的基本生物学差异。事实上，老鼠不是人类。然而，数据强烈表明，在小鼠饲养中普遍使用的环境条件削弱了我们在小鼠身上建立动脉粥样硬化模型的能力。这项探索性/发展性建议中的研究解决了一种新的假设，即实验室小鼠无处不在的严寒应激(出于非科学原因而系统地使用的实用“范例”--穿着衣服的人类操纵者的舒适性)深刻地影响了小鼠的生理和免疫学，直接损害了小鼠动脉粥样硬化的建模。值得注意的是，对冷应激的适应性反应涉及交感神经系统的持续激活和糖皮质激素的产生，这两者都有效地抑制了巨噬细胞的激活--巨噬细胞在动脉粥样硬化的所有阶段都是疾病发病的关键细胞。此外，据报道，在没有冷应激的情况下安置小鼠可以使它们的血浆脂蛋白谱“人性化”。因此，这方面的研究将直接和快速地检验这一假说--这一假说得到了文献中可获得的数据的有力支持--即目前的小鼠动脉粥样硬化模型从根本上受到与标准小鼠住所条件相关的慢性冷应激的破坏。如果这一假设是正确的，那么这一提议有一个明确而重要的成果--开发一种易于处理的、人源化的动脉粥样硬化小鼠模型，这将为动脉粥样硬化的研究提供一个急需的新工具。 生物学和治疗学。 公共卫生相关性：实验室小鼠是生物医学研究企业的核心。这项提议试图通过改变一个关键的、被忽视的环境变量：温度，来开发出更好的人类动脉粥样硬化的小鼠模型。我们假设，实验室小鼠普遍受到的冷应激(主要是非科学的 原因)损害了人类动脉粥样硬化性疾病的小鼠模型。一种易于处理的、人源化的动脉粥样硬化小鼠模型的发展将为动脉粥样硬化生物学和治疗的研究提供一个迫切需要的新工具。

DESCRIPTION (provided by applicant): Mice have triumphed as the in vivo experimental model system of choice in biomedical research. However, there are clear limitations to mouse models. The literature is full of therapeutic approaches that worked in mice but failed in humans. Further, mice often provide less than optimal mimics of the human diseases being modeled, atherosclerosis being a prime example. Compared to humans, mice are very resistant to atherosclerosis. In part, this is thought to be due to fundamental differences in lipoprotein metabolism between species. Available mouse models are thus based on dietary or genetic perturbations in lipoprotein metabolism; all have drawbacks. While mouse models have provided important insights into pathogenesis, fundamental biological and practical problems with available models have hindered translation of principles derived from mouse studies to human disease. As with other difficult-to-model diseases, this has been presumed to be due to basic biological differences between species. Indeed, mice are not humans. However, data strongly suggest that the environmental conditions ubiquitously employed in mouse husbandry impair our ability to model atherosclerosis in mice. The studies in this exploratory/developmental proposal address the novel hypothesis that the severe cold stress that laboratory mice are ubiquitously subjected to (a practical "paradigm" employed systematically for nonscientific reasons - the comfort of their clothed human handlers) profoundly affects mouse physiology and immunology in ways that directly impair the modeling of atherosclerosis in mice. Notably, the adaptive response to cold stress involves sustained activation of the sympathetic nervous system and glucocorticoid production, both of which potently suppress the activation of macrophages-cells critical to disease pathogenesis at all stages of atherosclerosis. Furthermore, housing mice in the absence of cold stress has been reported to "humanize" their plasma lipoprotein profiles. The studies in this will thus directly and rapidly test the hypothesis- one strongly supported by data available in the literature - that current mouse models of atherosclerosis are undermined, fundamentally, by the chronic cold stress associated with standard mouse housing conditions. If the hypothesis is correct, this proposal has a clear, important deliverable-the development of a tractable, humanized mouse model of atherosclerosis that would provide a critically needed novel tool for research into atherosclerosis biology and therapy. PUBLIC HEALTH RELEVANCE: Laboratory mice are central to the biomedical research enterprise. This proposal seeks to develop dramatically better mouse models of human atherosclerosis by altering a key, ignored environmental variable: temperature. We hypothesize that the cold stress that laboratory mice are ubiquitously subjected to (for largely non-scientific reasons) impairs the modeling of human atherosclerotic disease in mice. The development of a tractable, humanized mouse model of atherosclerosis would provide a critically needed novel tool for research into atherosclerosis biology and therapy.