MECHANISM OF INFLAMMATION IN ENVIRONMENTAL ENTERIC DYSFUNCTION

营养不良是贫困儿童健康成长和发展的最大障碍。它影响到1.5亿多5岁以下儿童，而且由于它大大增加了严重感染的脆弱性，它间接造成了全球儿童死亡总数的近一半-每年300多万人。营养不良使儿童无法发挥其在成长、发展和教育方面的潜力，使他们无法摆脱贫困，从而增加了他们的子女在艰苦环境中成长的风险。令人惊讶的是，即使为儿童提供健康的饮食，营养不良往往也不会好转。我们还不完全了解其中的原因，但这可能是由于一种称为环境肠道功能障碍（EED）的情况。患有EED的儿童肠道发炎，可能是由于生活在不卫生的环境中，不断接触致病细菌和其他微生物。炎症会阻止它们正确吸收营养物质，并且本身就有能量消耗，这意味着吸收的营养物质不能用于生长。我们对EED的根本原因的理解非常差。这部分是因为不进行活检很难确切地知道儿童肠道内发生了什么，而在资源有限的情况下，活检通常是不道德或不实用的。最近，我的合作者们找到了一种绕过这一限制的可能方法。他们已经确定，通过给实验室小鼠喂食营养不良的饮食并将其暴露于细菌混合物中，可以诱导出与EED非常相似的病症。本奖学金的目的是使用EED的“小鼠模型”，试图找出它究竟是如何产生的。1.数以百万计的细菌生活在我们的肠道内。它们被阻止进入我们的组织，并通过肠上皮细胞（IEC）形成的屏障对我们造成伤害。我将使用各种实验室技术来观察这种屏障在EED小鼠中的表现，并观察它是否允许肠道细菌进入我们的组织并激活白色血细胞（WBC，其作用是识别和对抗感染）。我将通过基因修饰诱导小鼠EED，改变IEC或WBC检测细菌的能力，以观察对设法进入我们组织的细菌的反应是好还是坏。我的怀疑（假设）是细菌穿过肠道屏障导致WBC的持续激活，这种激活对IEC没有帮助，恶化了它们维持肠道屏障的能力，并形成恶性循环。2.我将开发一个基于试管的系统，复制EED小鼠肠道中发生的事情，并使用它来检测WBC和IEC之间的信号传导，以确定可能干扰屏障功能的化学信号。我将使用遗传和药物为基础的方法，看看这些信号是否可以中断在试管系统和小鼠。我将评估这是否降低了小鼠EED的严重程度，并确保它不会增加感染的脆弱性。为了测试我的研究结果对人群的适用性，我将在赞比亚招募一组患有EED或健康（对照）的成年人。志愿者将接受内窥镜检查（在镇静和完全知情同意的情况下），我将使用活检样本复制EED小鼠中建立的试管系统。我将观察人类是否存在与小鼠相同的化学信号，并获得EED中肠道WBC发生的最详细的图片。我的长期工作目标是确定如何改变WBC（免疫）功能，以减轻EED造成的危害。通过摆脱EED，我们可以帮助支持贫困儿童的健康成长。

Malnutrition is the greatest barrier to healthy growth and development for children living in poverty. It affects more than 150 million children under 5 years old, and because it dramatically increases vulnerability to severe infection it is indirectly responsible for almost half of all global child deaths - more than 3 million every year. Malnutrition stops children from reaching their potential in growth, development, and education, preventing them from escaping poverty, and increasing the risk that their children, in turn, will grow up in hardship. Surprisingly, malnutrition often fails to get better even if children are provided with a healthy diet. We do not fully understand the reasons for this, but it may be due to a condition called Environmental Enteric Dysfunction (EED). Children with EED have inflamed intestines, possibly due to living in a unhygienic environments with constant exposure to disease-causing bacteria and other microorganisms. Inflammation prevents them from absorbing nutrients properly and has an energy cost in itself, meaning that nutrients which are absorbed can not be used for growth. Our understanding of the root cause of EED is remarkably poor. This is partly because it is difficult to know exactly what is happening in children's intestines without taking a biopsy, which would not usually be ethical or practical in resource-limited settings. Recently, my collaborators have found a possible way around this constraint. They have identified that a condition very similar to EED can be induced in laboratory mice by feeding them a malnourished diet and exposing them to a cocktail of bacteria. The objective of this Fellowship is to use this 'mouse model' of EED to try and find out exactly why and how it arises. 1. Millions of bacteria live inside our intestines. They are prevented from travelling into our tissues and causing us harm by the existence of a barrier, which is made by intestinal epithelial cells (IEC). I will use a variety of laboratory techniques to look at how well this barrier is performing in mice with EED and to see whether it is permitting intestinal bacteria to enter our tissues and activate white blood cells (WBC, whose role it is to identify and fight infection). I will induce EED in mice with genetic modifications that alter either IEC's or WBC's capacity to detect bacteria in order to see whether responding to bacteria that have managed to get into our tissues is good or bad. My suspicion (hypothesis) is that bacteria making it across the intestinal barrier lead to sustained activation of WBC, that this activation has unhelpful consequences for IEC, worsening their ability to sustain the intestinal barrier, and creating a vicious cycle. 2. I will develop a test-tube-based system that replicates what is happening in the intestine of a mouse with EED and use it to characterise signalling between WBC and IEC in order to pinpoint chemical signals that might interfere with barrier function. I will use genetic and drug-based approaches to see if these signals can be interrupted both in the test-tube system and in mice. I will assess whether this reduces the severity of EED in mice, and make sure that it does not increase vulnerability to infection.3. In order to test the applicability of my findings to human populations I will recruit a group of adults who either have EED or are healthy (controls) in Zambia. Volunteers will undergo an endoscopy (under sedation and with fully informed consent) and I will use biopsy samples to replicate the test-tube system established in EED mice. I will look to see if the same chemical signals are present in man as in mouse, and gain the most detailed picture yet of what happens to intestinal WBC in EED. The long-term aim of my work is to determine how to alter WBC (immune) function to ameliorate the harms caused by EED. By getting rid of EED we may help to support healthy growth of children living in poverty.