MECHANISM OF INFLAMMATION IN ENVIRONMENTAL ENTERIC DYSFUNCTION

点击翻译按钮获取中文摘要

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.