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，不分种族。虽然已知微生物和宿主相关因素对这种多因素条件有贡献，但其潜在的分子机制(S)尚不清楚。头皮屑被认为是一种温和的非炎症性疾病。数据表明有免疫参与，而转录组和脂组分析显示皮肤脂质水平失调，屏障脂水平降低。头皮屑感染皮肤中免疫细胞及其产物的变化可能会影响表皮角质形成细胞的脂质体，但这一点尚未被探索。我们已经表明，头皮屑感染皮肤减少了固有淋巴样细胞和树突状细胞的数量，增加了T细胞的数量，并增加了具有抗炎、免疫抑制和止痒特性的脂质介质的产生。这些发现表明，皮肤脂质介质可能在缓解头皮屑影响皮肤中观察到的炎性应激方面发挥作用。假设、目的和目的我们将探讨一种假设，即免疫渗透/激活增加会影响头皮屑中角质形成细胞的功能，导致生物活性脂质的产生改变，从而可能缓解炎症环境。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体，并利用实验数据建立“炎症应激下的角质形成细胞”的体内模型。我们将使用我们的二十烷类化合物的电子模型，并进一步改进它来表示头皮角质形成细胞-免疫细胞的反应，就像在头皮屑中发现的那样。这将创造一种细胞-细胞相互作用的电子预测工具，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。培训学生将接受最先进的细胞培养、脂质提取、质谱学、RNAseq、计算系统生物学和生物信息学方面的培训。他们还将在英国联合利华的研发实验室进行实习，并将深入了解科学如何发展到技术，然后发展到标记上的产品，并了解专利和知识产权。学生将从导师与学术、临床和工业团体的合作中受益，并有机会参加国家和国际会议和会议。与BBSRC的职权范围和DTA主题保持一致该项目与BBSRC的战略重点领域--生物科学促进健康和DTP主题--世界级生物科学相一致。该项目将探索免疫细胞和表皮角质形成细胞之间的相互作用，旨在了解皮肤炎和免疫反应对头皮屑影响皮肤脂体的影响；这将促进分子和细胞水平的免疫学研究。了解类脂在头皮屑所涉及的免疫反应中的作用，将有助于解决人类健康问题。头皮屑是一种疾病，无论种族如何，都会影响很大一部分人。利用质谱脂组学的实验数据，我们将采用、改进和验证一个先进的电子计算表皮角质形成细胞-免疫细胞-细胞相互作用模型。这与BBSRC使用“基于系统的方法”的战略计划是一致的。计算和生物信息学技术在高质量定量生物数据(质谱学，RNAseq)中的应用，以及在计算机模型构建和验证(微分方程式，蒙特卡罗整体模型)中的应用，支持了“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'.