Developing an in silico model of the scalp keratinocyte lipidome in dandruff

头皮屑是一种常见的疾病，影响10-50%的人口，无论种族如何。尽管已知微生物和宿主相关因素促成这种多因素条件，但尚未了解潜在的分子机制。头皮屑被认为是一种轻微的非炎症性疾病。数据表明，有免疫参与，而转录组学和脂质组学分析显示皮肤脂质失调水平与屏障脂质水平降低。这是可能的，在头皮屑影响皮肤的免疫细胞及其产品的变化可能会影响表皮角质形成细胞的脂质组，但这还没有被explored.We已经表明，头皮屑影响头皮皮肤的先天淋巴细胞和树突状细胞的数量减少，T细胞的数量增加，并增加生产具有抗炎免疫抑制和抗炎症特性的脂质介质。这些发现表明皮肤脂质介质可能在调节头皮屑影响的皮肤中观察到的炎症应激中起作用。假设，目的和目标我们将探讨增加免疫浸润/激活影响头皮屑中角质形成细胞功能，导致生物活性脂质产生改变，从而减轻炎症环境的假设。我们建议在体外研究表皮角质形成细胞与免疫细胞相互作用后的脂质组，并使用实验数据创建“炎症应激下的角质形成细胞”的计算机模型。我们将使用我们的类二十烷酸计算机模型，并进一步完善它，以代表头皮角质形成细胞免疫细胞反应，如头皮屑中所发现的。这将为细胞-细胞相互作用创造一种计算机预测工具，它可能成为皮肤炎症反应的预测工具，并可能取代产品开发早期阶段使用的实验模型。培训学生将接受细胞培养，脂质提取，质谱脂质组学，RNASeq，计算系统生物学和生物信息学的最先进的培训。他们还将在英国联合利华研发实验室进行实习，并将深入了解科学如何发展成为技术，然后发展成为市场上的产品，并了解专利和知识产权。学生将受益于导师与学术，临床和工业团体的合作，并有机会参加国家和国际会议和会议。与BBSRC职权范围和DTA主题保持一致该项目与BBSRC的生物科学健康战略优先领域和DTP主题世界级支撑生物科学保持一致。该项目将探索免疫细胞和表皮角质形成细胞之间发生的相互作用，旨在了解皮肤炎症和免疫反应对头皮屑影响皮肤脂质组的影响;这将推进“分子和细胞水平的免疫学研究”。了解脂质在头皮屑所涉及的“免疫反应”中的作用，头皮屑是一种影响大部分人口的疾病，无论种族如何，将解决“人类健康问题”。使用质谱脂质组学的实验数据，我们将适应，完善和验证表皮角质形成细胞-免疫细胞-细胞相互作用的高级计算机模拟模型。这与BBSRC使用“基于系统的方法”的战略计划相一致。将计算和生物信息学技术应用于高质量的定量生物数据（质谱，RNAseq）和计算机模型构建和验证（微分方程，Monte Carlo集成建模），支持“数字生物学”的发展。

Dandruff is a common condition, affecting 10-50% of the population, irrespective of ethnicity. Although microbial and host-related factors are known to contribute to this multifactorial condition, the underlying molecular mechanism(s) are not yet understood. Dandruff is considered a mild non-inflammatory condition. Data suggest that there is immune involvement, whilst transcriptomics and lipidomics analyses show a level of cutaneous lipid dysregulation with reduced levels of barrier lipids. It is possible that changes in immune cells and their products in dandruff-affected skin might influence the lipidome of epidermal keratinocytes, but this has not yet been explored.We have shown that dandruff-affected scalp skin has decreased numbers of innate lymphoid and dendritic cells, increased numbers T cells, and increased production of lipid mediators with anti-inflammatory immunosuppressive and anti-pruritic properties. These findings indicate that skin lipid mediators may have a role in moderating the inflammatory stress observed in dandruff-affected skin. Hypothesis, Aim and ObjectivesWe will explore the hypothesis that increased immune infiltrate/activation affects keratinocyte function in dandruff, leading to altered production of bioactive lipids that might mitigate the inflammatory environment. We propose to study the lipidome of epidermal keratinocytes following interactions with immune cells in vitro and use the experimental data to create an in silico model of the 'keratinocyte under inflammatory stress'. We will use our in silico model of eicosanoids and further refine it to represent the scalp keratinocyte-immune cell reactions, as found in dandruff. This will create an in silico predictive tool for cell-cell interactions, that could become a predictive tool for skin inflammatory reactions and may replace experimental models used in the early stages of product development. TrainingThe student will receive state-of-the-art training in cell culture, lipid extractions, mass spectrometry lipidomics, RNASeq, computational systems biology and bioinformatics. They will also undertake placements in a UK Unilever R&D lab and will develop insight into how science develops into technologies and then into products on the marker, and gain an understanding of patenting and intellectual property. The student will benefit from the supervisors' collaborations with academic, clinical and industrial groups, and get the opportunity to attend national and international meetings and conferences.Alignment with the BBSRC remit and DTA themesThe project aligns with the BBSRC's strategic priority area of Bioscience for Health and the DTP theme World Class Underpinning Biosciences. The project will explore the interactions occurring between immune cells and epidermal keratinocytes aiming to understand the impact of cutaneous inflammatory and immune reactions on the lipidome of dandruff-affected skin; this will advance 'immunological research at molecular and cellular level'. Understanding the role of lipids in the 'immune responses' involved in dandruff, a condition that affects a large proportion of the population irrespective of ethnicity, will be addressing a 'human health issue'. Using experimental data from mass spectrometry lipidomics we will adapt, refine and validate an advanced computational in silico model of epidermal keratinocyte-immune cell-cell interactions. This aligns with the BBSRC's strategic plan in using 'systems-based approaches'. The application of computational and bioinformatics techniques to high-quality quantitative biological data (mass spectrometry, RNAseq) and in silico model construction and validation (differential equations, Monte Carlo ensemble modelling), support the development of 'digital biology'.