An investigation of circadian rhythms in psoriasis skin and time-of-day dependent response to ultraviolet B radiation

人类有一个内置的生物钟，控制着24小时内不同基因和蛋白质的表达，我们称之为昼夜节律。皮肤是人体最大的器官，是与环境的重要界面。我们的环境暴露在白天和黑夜之间存在巨大的差异，包括我们从太阳获得的紫外线（UV）辐射量，身体伤害的风险，如割伤和烧伤，温度变化和皮肤干燥。为了帮助解决这个问题，皮肤细胞有自己的时钟，我们相信它已经进化到帮助预测和更好地适应我们的环境。对小鼠的研究表明，皮肤生长和阳光损伤的风险在一天中各不相同。我们知道，人类皮肤的生长也在一天中变化，但我们不知道我们对阳光的敏感度是否也在变化。虽然太多的阳光对我们的皮肤是危险的，但几千年来我们已经知道它可以改善牛皮癣等皮肤病。牛皮癣是一种常见的皮肤病，可以致残，以及导致社会排斥。它表现为皮肤可见区域的红色，厚和鳞状斑块。光疗是将太阳辐射的安全部分照射在皮肤上，是治疗银屑病的好方法，因为它相对安全有效，人们通常更喜欢它而不是片剂治疗。然而，它并不适用于每个人，所以我们将继续研究这一点，并找出原因。观察牛皮癣皮肤的生物钟，看看它是否存在，并像非牛皮癣皮肤一样正常运作2。发现新的基因周期在一天的过程中牛皮癣皮肤3。观察银屑病斑块在治疗后病情好转时昼夜节律的变化。为了研究银屑病皮肤是否在上午比下午对紫外线辐射更敏感，在项目的第一部分，我将只观察银屑病患者和非银屑病患者的单个皮肤细胞，并“实时”监测昼夜节律钟。在下一部分，我将在上午和下午从患者的银屑病斑块中取6 mm的皮肤活检，有和没有紫外线辐射（每例患者四次活检）。将对该皮肤进行染色，以帮助比较不同时间点之间UV辐射的影响。这些皮肤也将被送去进行基因表达谱分析，以观察细胞在早上和下午的行为是否不同。这部分研究需要16名患者，这是根据我们收集的早期数据精确计算的。最后，我将分析已经从一项名为PSORT的数百万磅研究中获得的基因表达数据（相关治疗的患者分层和优化），其中120多名银屑病患者在使用一种称为生物制剂的不同药物治疗的过程中进行了皮肤活检。这些活组织检查记录了他们的时间，这意味着我可以在更大的队列中比较基因表达，看看当他们的银屑病清除时会发生什么变化。首先，牛皮癣是非常常见的，所以任何提高我们对牛皮癣的了解都可以帮助世界各地的许多人。其次，这个项目有可能改变我们提供光疗的方式，这意味着我们可以改善对银屑病患者的护理。最后，学习和应用昼夜节律有更广泛的应用。时间疗法-在一天中的特定时间进行治疗以获得更好的结果-正在成为医疗保健领域一个令人兴奋的新概念。我们对如何进行这项研究的了解可以应用于其他疾病，也可以将时间疗法应用于其他疾病。

Humans have a built-in body clock that controls the expression of different genes and proteins over a 24-hour period, which we call our circadian rhythms. The skin is the largest organ in the body and forms an important interface with the environment. There is a huge variation between the day and night in our environmental exposures, including the amount of ultraviolet (UV) radiation we get from the sun, the risk of physical injury like cuts and burns, temperature changes and drying out of the skin. To help with this, the skin's cells have their own clock which we believe has evolved to help predict and better adapt to our environment. Research studies in mice have shown that skin growth and risk of damage from sunlight varies over the course of the day. We know that human skin growth also varies over the day but we don't know whether our sensitivity to sunlight varies too.Whilst too much sunlight is dangerous for our skin, we have known for thousands of years that it can improve skin diseases like psoriasis. Psoriasis is a common skin condition which can be disabling, as well as leading to social rejection. It presents as red, thick and scaly plaques on visible areas of the skin. Phototherapy, which is where a safe part of the radiation from the sun is shone on the skin, is a good treatment for psoriasis because it is relatively safe and effective and often people prefer it to tablet treatments. However, it doesn't work for everyone, so we are continuing to look into this and work out why.The aims of this study are:1. To look into the circadian clock in psoriasis skin to see whether it is present and functions normally like in non-psoriasis skin2. To discover new genes that cycle over the course of the day in psoriasis skin3. To see how circadian rhythms change in psoriasis plaques as they get better with treatment4. To investigate whether psoriasis skin is more sensitive to UV radiation in the morning compared with the afternoonFor the first part of the project, I will just look at the individual skin cells of patients with and without psoriasis and monitor the circadian clock in "real-time".For the next part, I will take small, 6mm biopsies of skin from the psoriasis plaques of patients in the morning and afternoon, with and without UV radiation (four biopsies per patient). This skin will be stained to help compare the effects of UV radiation between time points. This skin will also be sent for gene expression profiling and analysis performed to see if the cells are behaving differently in the morning and afternoon. Sixteen patients will be required for this part of the study and this has been precisely calculated based on earlier data we have gathered.Lastly, I will analyse gene expression data that has already been taken from a large multimillion pound study called PSORT (Psoriasis Stratification and Optimisation of Relevant Therapies), in which over 120 patients with psoriasis gave skin biopsies over the course of their treatment with a different medication called a biologic. These biopsies have the time they were taken recorded which means I can compare gene expression in a larger cohort and see what changes happen as their psoriasis clears.I think this research is very important for three reasons. Firstly, psoriasis is very common, and so anything that improves our understanding of psoriasis can help many people worldwide. Secondly, this project has the potential to change the way we deliver phototherapy, meaning we can improve care of people with psoriasis. Lastly, learning about and applying circadian rhythms has a wider application. Chronotherapy - giving treatments at a particular time in the day for better outcomes - is emerging as a new and exciting concept in healthcare. What we learn about how we carry this research can be applied to other diseases to apply chronotherapy to those too.