Better mouse models of disease: Humanizing experimental atherosclerosis

描述（由申请人提供）：小鼠已成功地成为生物医学研究中选择的体内实验模型系统。然而，小鼠模型有明显的局限性。文献中充满了在小鼠身上有效但在人类身上失败的治疗方法。此外，小鼠通常提供不太理想的人类疾病的模拟模型，动脉粥样硬化是一个主要的例子。与人类相比，小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脂蛋白代谢的饮食或遗传扰动;所有这些都有缺点。虽然小鼠模型提供了重要的发病机制的见解，基本的生物学和实际问题与现有的模型，阻碍了翻译的原则，从小鼠研究到人类疾病。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。的确，老鼠不是人类。然而，数据强烈表明，在小鼠饲养中普遍采用的环境条件损害了我们在小鼠中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提出了一个新的假设，即实验室小鼠普遍受到的严重冷应激（一种出于非科学原因系统采用的实用“范式”--穿着衣服的人类处理者的舒适度）深刻影响了小鼠的生理学和免疫学，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在动脉粥样硬化的所有阶段对疾病发病机制至关重要的巨噬细胞的激活。此外，据报道，在没有冷应激的情况下圈养小鼠可以使其血浆脂蛋白谱“人源化”。因此，这方面的研究将直接和快速地检验这一假设--这一假设得到了文献中现有数据的有力支持--即目前的动脉粥样硬化小鼠模型从根本上被与标准小鼠饲养条件相关的慢性冷应激所破坏。如果假设是正确的，这个建议有一个明确的，重要的交付-一个易于处理的，人性化的动脉粥样硬化小鼠模型的发展，将提供一个迫切需要的新工具，研究动脉粥样硬化 生物学和治疗

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.