Cellular Mediator of Thermoregulatory Responses

肥大细胞是复杂的免疫细胞，含有许多介质，尽管它们最出名的是它们在过敏（产生组胺）和外周炎症（被虫子咬后肿胀和发红）中的作用。令人惊讶的是，肥大细胞存在于大脑中，在特定的正常和病理条件下，肥大细胞的数量会增加。它们在大脑中靠近血管的位置表明，肥大细胞可以调节行为和生理反应，包括体温调节。初步研究表明，阻断肥大细胞的激活可以改变由病原体进入人体引起的高温反应。我们已经生成肥大细胞缺陷小鼠，以探索这些细胞对生理上适当的免疫反应的必要性。实验包括注射脂多糖（细菌细胞的一部分）并测量产生的反应（即体温，运动活动）。这种注射可以刺激免疫系统，使正常小鼠发烧，就像对细菌的反应一样。将研究三个实验组：正常，肥大细胞缺陷和年龄匹配的成年缺陷小鼠，其中肥大细胞已被重建。预计肥大细胞缺陷小鼠在注射细菌细胞壁后几乎没有温度变化，而重组动物的反应应恢复正常。后续研究将探索肥大细胞是如何导致发烧的。肥大细胞参与体温调节的发现代表了免疫细胞影响生理和行为的革命性实例。此外，大脑中肥大细胞的贡献可能会改变目前认为大脑是免疫特权部位的想法，并进一步支持大脑中非神经元细胞有助于控制行为的观点。本项目将为本科生和研究生在实验室提供独特的训练机会。

Mast cells are complex immune cells containing many mediators, though they are best known for their role in allergies (produce histamine) and peripheral inflammation (swelling and redness after a bug bite). Surprisingly, mast cells are found in the brain, and the number of brain mast cells increase under specific normal and pathological conditions. Their location in the brain, near blood vessels, suggests that mast cells are poised to regulate behavioral and physiological responses, including body temperature regulation. Pilot work suggests that blocking mast cell activation can alter the elevated temperature response caused by a pathogen entering the body. We have generated mast cell deficient mice to explore the necessity of these cells for a physiologically appropriate immune response. Experiments involve injecting lipopolysaccharide (a piece of a bacteria cell) and measuring the resulting responses (i.e. body temperature, locomotor activity). This injection acts as a stimulus for mounting the immune system, causing a fever in normal mice, just like the reaction to bacteria. Three experimental groups will be studied: normal, mast cell deficient, and age matched adult deficient mice in which the mast cells have been reconstituted. The mast cell deficient mice are predicted to show little to no temperature change following injection of bacterial cell wall, while the response should be restored to normal in the reconstituted animals. Follow-up studies will explore how mast cells contribute to fever. The discovery that mast cells participate in thermoregulation would represent a revolutionizing instance of immune cells impacting physiology and behavior. In addition, the contribution of mast cells in the brain could change the current thinking that the brain is an immune-privileged site and further support the notion that non-neuronal cells in the brain contribute to the control of behavior. This project willprovide unique training opportunities for undergraduate and graduate students in the lab.