Connexin 26-mediated breathing control by the healthy and obese brain

人类每天产生大约1公斤二氧化碳。二氧化碳溶解在血液中，除非其水平得到精确控制，否则将导致血液酸度的致命变化。大脑中存在的对二氧化碳敏感的细胞控制着呼吸的深度，以精确地调节血液和身体中的二氧化碳水平。许多人类疾病严重影响了对二氧化碳水平的调节。其中一种情况就是肥胖。40%的肥胖患者存在肥胖低通气综合征。这些患者呼吸不够深，无法排出足够的二氧化碳，并损害了对二氧化碳敏感的呼吸调节。因此，他们的血液更酸性，他们感到困倦，白天昏昏欲睡，很容易筋疲力尽，他们的睡眠模式受损，导致工作能力下降，这是一个恶性循环。其他人类疾病，例如影响约1%中年人的Chiari综合症，会导致严重的衰弱问题，从头痛到吞咽、睡眠和呼吸能力障碍，患者患有呼吸暂停，夜间睡眠时呼吸浅且不规律。我们最近在大脑表面发现了负责感知二氧化碳的关键细胞，这为每个人的大脑如何感知二氧化碳这个根本问题提供了意想不到的新线索，并为理解上述医疗条件提供了新的途径。这些细胞内的一种基本分子，称为连接蛋白26的膜通道，帮助这些细胞感知二氧化碳水平。当通过一种新的遗传方法使不超过25个特定细胞的一小部分细胞失去连接蛋白26基因时，人体调节呼吸以应对更高的二氧化碳水平(与某人呼吸中的二氧化碳水平相当)的能力降低了40%。这25个关键细胞在啮齿类动物的青春期左右发育，保留到中年后期，然后在老年时消失，从而在一生中在特定的时间窗口发挥作用。连接蛋白26在脑干周围的其他细胞中也很活跃，但它们与呼吸有关的功能尚不清楚。我们建议在转基因啮齿动物的其他特定细胞组中灭活该基因，以测试这些细胞是否以及如何调节呼吸对二氧化碳的敏感性。我们已经发现，这些二氧化碳感应细胞携带着控制体重的重要途径(瘦素途径)的受体。在肥胖患者中，瘦素途径受损。这意味着，我们可能已经发现了肥胖机制和这些患者呼吸调节缺陷之间缺失的一环：由于瘦素信号受损，二氧化碳感应细胞可能无法很好地感知二氧化碳。随着我们现在可以直接在动物身上观察和表征这些非常重要的细胞的特性，我们可以问，年轻时高脂肪/高热量饮食导致的肥胖是否会影响这些关键的二氧化碳感觉细胞的发育和特性。我们建议通过改变我们已经发现的二氧化碳敏感细胞中的瘦素信号来进一步实验测试这一假说，看看我们是否可以在啮齿动物身上重现人类肥胖低呼吸综合征。有了这样的动物模型，人们就可以开发和测试帮助患者呼吸的新药。我们的工作承诺与人类有很大的相关性。如果我们在青春期摄入过多的糖，这些重要的感受器细胞会死亡吗？他们是如何受到影响的，这是永久性的吗？它能通过饮食或药物逆转吗？它们开启了哪些基因？如果我们知道这些必要的二氧化碳感觉细胞是如何受饮食影响的，我们就可以更准确地推荐人类青春期和青春期的正确食物类型。呼吸对我们所做的一切都是必不可少的，无论我们是清醒的还是睡眠的，肥胖症是一种日益严重的全球健康流行病。通过将发育遗传学和生理学联系起来，该项目承诺为广大社区的身心健康提供长期利益。

Humans produce about 1 kg of CO2 every day. CO2 dissolves in blood and will cause fatal changes in blood acidity unless its levels are precisely controlled. CO2-sensitive cells, present in the brain, control the depth of breathing to precisely regulate the level of CO2 in the blood and body.Many human illnesses seriously affect to regulate breathing in response to levels of CO2. One of these conditions is obesity. 40% of obese patients have Obesity Hypoventilation Syndrome. These patients cannot breathe deeply enough to expel sufficient CO2, and have impaired CO2-sensitive regulation of breathing. Their blood is therefore more acidic, they feel sleepy, drowsy during daytime, exhaust easily and they have impaired sleep patterns, which result in reduced ability to work, a vicious cycle. Other human conditions, for example Chiari Syndrome, which affects around 1% of people in middle age, leads to severe debilitating problems, ranging from headaches to inabilities to swallow, sleep and breathe, patients suffer from apneas, shallow and irregular breathing during sleep at night. We have recently discovered key cells responsible for sensing of CO2 on the brain's surface, which sheds unexpected new light onto the fundamental question how everybody's brain senses CO2 and provides new avenues to understand the medical conditions mentioned above. An essential molecule inside these cells, a membrane channel called Connexin26, helps these cells to sense CO2 levels. When only a small group of specific cells, no more than 25, are made to lose the Connexin26 gene by a novel genetic method, the ability of the body to regulate breathing in response to higher CO2 levels (comparable to the CO2 levels inside someone's breath) is reduced by 40%. These 25 critical cells develop around puberty in rodents, are retained into late middle age and then lost in old age, thus act in a specific time window during life.Connexin 26 is also active in other cells around the brainstem, however their function in relation to breathing is unknown. We propose to inactivate this gene in further specific groups of cells in transgenic rodents to test whether and how these cells regulate the sensitivity of breathing to CO2. We have discovered that these CO2-sensing cells carry receptors for an important pathway that controls body weight (the leptin pathway). In obese patients, the leptin pathway is impaired. This means that we may have found a missing link between the mechanisms underlying obesity, and the defective regulation of breathing in these patients: the CO2-sensing cells may not be able to sense CO2 well enough as a consequence of impaired leptin signalling. As we can now observe and characterize the properties of these very important cells in animals directly, we can ask whether obesity, induced by high fat/calorie diet during young age, affects the development and properties of these critical CO2-sensory cells. We propose to test further this hypothesis experimentally by altering leptin signalling specifically in the CO2-sensing cells that we have discovered, to see whether we can recapitulate the human Obesity Hypoventilation Syndrome in rodents. With such animal model one can develop and test new drugs that help patients breathe. Our work bears the promise of great relevance to humans. Do those important sensor cells die if we eat too much sugar during adolescence? How are they affected, is that permanent? Can it be reversed by diet or medicines? Which genes do they turn on? If we know how these essential CO2 sensory cells are affected by diet, we can be much more precise on recommending the right types of food to be eaten during adolescence and puberty in humans. Breathing is essential for all we do, whether we are awake or sleep and obesity is a growing global health epidemic. By linking developmental genetics and physiology this project promises to provide long-term benefit to the physical and mental well-being of the wider community.