Better mouse models of disease: Humanizing experimental atherosclerosis

描述（由申请人提供）：小鼠已成为生物医学研究中首选的体内实验模型系统。然而，小鼠模型有明显的局限性。文献中充满了对老鼠有效但对人类无效的治疗方法。此外，小鼠通常不能很好地模拟被模拟的人类疾病，动脉粥样硬化就是一个典型的例子。与人类相比，老鼠对动脉粥样硬化有很强的抵抗力。在某种程度上，这被认为是由于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饮食或基因对脂蛋白代谢的干扰；它们都有缺点。虽然小鼠模型提供了对发病机制的重要见解，但现有模型的基本生物学和实际问题阻碍了从小鼠研究中获得的原理转化为人类疾病。与其他难以建模的疾病一样，这被认为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损害了我们在小鼠中模拟动脉粥样硬化的能力。本探索性/发展性提案中的研究解决了一个新的假设，即实验室小鼠普遍遭受的严重冷应激（一种实用的“范式”，系统地用于非科学原因-穿着衣服的人类处理者的舒适度）以直接损害小鼠动脉粥样硬化模型的方式深刻影响小鼠的生理和免疫。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，这两者都能有效地抑制巨噬细胞的激活——巨噬细胞是动脉粥样硬化所有阶段疾病发病的关键细胞。此外，据报道，在没有冷应激的情况下饲养小鼠可以使其血浆脂蛋白谱“人性化”。因此，这项研究将直接和快速地验证一个假设——一个得到文献数据有力支持的假设——即当前的小鼠动脉粥样硬化模型从根本上被与标准小鼠住房条件相关的慢性冷应激破坏了。如果这个假设是正确的，那么这个建议就有了一个明确的、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研究提供一个急需的新工具

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.