Kindlin and EGFR control convergent pathways to regulate epithelial cell function

这项研究涉及两种我们知道在皮肤起泡疾病患者中没有正确控制的蛋白质。这些蛋白质被称为Kindlin-1和表皮生长因子受体(或EGFR)。我们已经知道，皮肤中缺乏Kindlin-1会导致Kindler综合征，这是一种罕见的遗传病，会导致皮肤起泡，有时还会导致皮肤癌。我们最近还发现了一组新的EGFR蛋白缺陷患者，这类似地导致皮肤脆弱。我们最近对这两种蛋白质的研究有力地表明，在患者中观察到的临床缺陷部分是由类似的过程出错引起的。这种缺陷主要存在于细胞附着在皮肤周围蛋白质上的能力上。黏附过程的正常运作对健康至关重要，如果黏附过程出错，可能发生的疾病包括皮肤脆弱、牛皮癣、癌症、免疫力下降和炎症。我们现在要做的研究包括更详细地分析Kindlin-1和EGFR的功能。我们首先想要确切地知道这些蛋白质是如何共同作用于正常皮肤功能的。我们计划使用一些生化和显微镜技术来回答这样的问题：这两种蛋白质在细胞中是否结合在一起；其中一种蛋白质的缺失如何扰乱细胞与其周围蛋白质的粘连能力，以及这种蛋白质复合体的共同目标如何也控制这一过程？在我们的研究中，我们还希望建立更复杂的模型，使我们能够研究Kindlin-1和EGFR在完整生物体中的功能。我们之所以这样做，是因为我们想要找出这些蛋白质在一个更真实的环境中的表现，在那里有其他细胞和组织可能改变这些蛋白质的行为。为此，我们将使用果蝇表皮起泡的一个非常有特点的模型。这些动物比小鼠更容易、更便宜、更快地工作，并且拥有我们计划研究的所有基因/蛋白质的版本，因此是我们实验的理想选择。通过结合我们从细胞、人体组织和果蝇模型实验中获得的信息，我们还可以开始计划使用基因、蛋白质和药物进行潜在的纠正治疗，这项工作可能会在未来改善患者的状况。这项工作可以减少皮肤起泡，改善Kindlin-1或EGFR缺陷家庭的生活质量。这项工作有望扩大我们对细胞与周围组织的黏附以及健康皮肤的生理维护这一根本重要的基础科学课题的了解。

This research relates to two proteins that we know are not correctly controlled in patients with skin blistering disease. These proteins are called Kindlin-1 and Epidermal Growth Factor Receptor (or EGFR). We already know that lack of Kindlin-1 in the skin leads to Kindler Syndrome - a rare genetic disorder that results in skin blistering and sometimes leads to skin cancer. We have also recently identified a new group of patients that have defective EGFR protein and this similarly results in fragile skin. Our recent research on these two proteins strongly suggests that the observed clinical defects in the patients are partly caused by similar processes going wrong. This defect is mainly in the ability of cells to stick, or 'adhere' to the proteins that surround them in the skin. Normal functioning of the adhesion process is critical to health, and if it goes wrong, the sort of diseases that might occur include skin fragility, psoriasis, cancer, reduced immunity and inflammation. The research we would like to do now involves analysing Kindlin-1 and EGFR function in more detail. We firstly want to know precisely how these proteins work together to contribute to normal skin function. We plan to use a number of biochemical and microscopy techniques to answer questions such as: do these two proteins bind together in cells; how does loss of one or the other upset the ability of cells to adhere to proteins around them, and how do the common 'targets' of this protein complex also control this process? In our research we would also like to create more complex models to allow us to study Kindlin-1 and EGFR function in an intact organism. The reason we want to do this is because we would like to find out how these proteins behave in a more 'real' setting where there are other cells and tissues that might alter how these proteins behave. We will use a very well characterized model of epidermal blistering in the Fruitfly for this purpose. These animals are much easier, cheaper and faster to work with than mice and have versions of all of the genes/proteins we are planning to study, so are ideal for our experiments. By combining the information we get from experiments in cells, human tissues and the Fruitfly model, we can also start to plan potential corrective treatments with genes, proteins and drugs, work that could lead to improvements for patients in the future. Such work could lead to less skin blistering and improved quality of life in this and other families that have defects in Kindlin-1 or EGFR. The work is expected to expand our knowledge of the fundamentally important basic science topic of cell adhesion to surrounding tissues as well as the physiological maintenance of healthy skin.