Activation of the Inflammasome in Skin by Malassezia fungal species

关键词：炎性体皮炎先天免疫摘要：炎症是许多重要皮肤疾病的基础。最近的研究强调了炎症在导致极其常见的头皮状况头皮屑中的重要性。虽然炎症最初可以帮助修复受损的皮肤，但持续的炎症反应会使损伤永久化，导致上皮细胞更新增加，上皮细胞通透性屏障功能下降，这是头皮屑中皮肤功能异常的特征。这种炎症反应的触发因素尚不清楚，但许多证据表明马拉色菌属的真菌皮肤共生在启动和延续这种情况中的重要性。马拉色菌在皮肤中产生炎症反应的一种机制是通过激活炎性体。炎性小体是一个多亚基蛋白平台，导致细胞因子白介素-1 β (il -1 β)的加工和激活。在头皮屑患者体内检测到的il -1 β含量增加，因此可能在这种情况的发展中起重要作用。我们假设马拉色菌对炎症小体的激活是头皮屑中炎症反应的一个重要因素。我们有以下目标：1。目的：探讨球形马拉色菌激活人角化细胞炎性体的能力。确定这些真菌激活的炎性体的组成。探讨皮脂和真菌代谢产物在炎性小体活化中的相互作用。学员将接受以下培训：野生型和选择敲除小鼠的原代巨噬细胞和其他细胞的组织培养。免疫印迹和免疫方法。CRISPR/Cas9基因编辑。单细胞流式细胞术。低温电子显微镜用于炎性体的超微结构分析。系统生物学的方法是了解促使细胞激活炎性体的因素。

Studentship strategic priority area:Basic Bioscience Underpinning HeathKeywords: Inflammasome Dermatitis Innate ImmunityAbstract: Inflammation underlies many important skin conditions. Recent work has highlighted the importance of inflammation in driving the extremely common scalp condition of dandruff. Although inflammation can act initially to help repair damaged skin, a persistent inflammatory response can perpetuate damage, leading to increased epithelial turnover and decreased epithelial permeability barrier function that characterises the abnormal skin function in dandruff. Triggers to this inflammatory response are not clear, but much evidence shows the importance of the fungal skin commensal of the genus Malassezia in initiating and perpetuating this condition. One mechanism by which Malassezia could produce an inflammatory response in skin is through activation of the inflammasome. The inflammasome is a multisubunit protein platform that leads to processing and activation of the cytokine interleukin-1beta (IL-1beta). IL-1beta is detected in increased amounts in dandruff sufferers and thus may play an important role in the development of this condition. We hypothesise that activation of the inflammasome by Malassezia spp. is an important factor in initiating and propagating inflammatory responses in dandruff. We have the following aims:1. To define the ability of Malassezia globosa and restricta to activate the inflammasome in human keratinocytes.2. To determine the composition of the inflammasome activated by these fungi.3. To explore the interactions of sebum lipids and fungal metabolites on inflammasome activation.The student will receive training in the following:. Tissue culture of primary macrophages and other cells derived for wild type and select knockout mice. Western blotting, and immunological methods . CRISPR/Cas9 gene editing . Single cell flow cytometry . Cryoelectron microscopy for ultrastructural analysis of the inflammasome. Systems biology approaches to understand the factors that tip the cell to activate the inflammasome.