Understanding dynamic immune responses within a fluidic 3D skin equivalent model

皮肤是一个复杂的多细胞组织，由上皮细胞、成纤维细胞、血管、神经和树突状细胞组成。循环免疫细胞和组织驻留皮肤细胞之间的动态通信协调了对感染的反应，以及组织修复和再生。虽然现有的器官型皮肤模型复制了上皮和间质的基本双层结构，但模拟与免疫系统的复杂和动态相互作用已被证明极具挑战性。因此，拟议的博士项目旨在开发具有循环免疫细胞流体输送的3D人体皮肤模型，并研究对化学刺激物和细菌产物的动态反应。这个跨学科博士研究生的总体目标是通过开发一种新的免疫反应器官型模型，获得对皮肤内人类特异性炎症反应的新见解。该项目将构建并验证一个双室模型，该模型由一个3D器官型皮肤结构和一个由灌注细胞培养基连接的免疫室组成。具体目标包括：1。在市售的流体平台（Kirkstall Ltd, QV600）中建立人体皮肤的三维器官型模型。当中性粒细胞、单核细胞或巨噬细胞通过系统灌注时，描述免疫浸润和常驻皮肤细胞（角质形成细胞和成纤维细胞）的反应。分析免疫和常驻皮肤细胞对化学刺激物和应用于皮肤表面的纯化细菌产品的动态反应（迁移、增殖和分化）。通过分析细胞因子释放（Luminex）和RNAi和小分子的功能抑制，研究该平台内参与皮肤免疫系统串扰的分子介质。该项目的成功完成将建立具有免疫反应能力的下一代人体皮肤模型。该平台将成为了解人类特异性皮肤生物学以及测试和开发新化合物和治疗方法的有力工具。这个跨学科的学生将提供皮肤生物学、3D培养模型、生物工程和免疫学方面的高级培训。博士的监督和培训将由在这些领域具有专业知识的学者管理，学生将受益于暴雪最先进的设施。此外，学生将在Kirkstall有限公司进行为期3个月的工业实习，这是一家总部位于英国的中小企业，为一系列不同的组织模型开发流体培养系统。在这里，学生将获得流体系统及其在不同组织和疾病模型中的应用方面的额外经验。学生将进一步发展产品开发、商业化、沟通和营销方面的可转移技能。

The skin is a complex, multicellular tissue comprised of epithelial cells, fibroblasts, blood vessels, nerves, and dendritic cells. Dynamic communication between circulating immune cells and tissue-resident skin cells orchestrates the response to infection, as well as tissue repair and regeneration. While existing organotypic skin models replicate the basic bi-layered structure of the epithelium and mesenchyme, modelling the complex and dynamic interaction with the immune system has proven extremely challenging. The proposed PhD project therefore aims to develop a 3D human skin model with fluidic delivery of circulating immune cells and investigate the dynamic responses to chemical irritants and bacterial products.The overall aim of this interdisciplinary PhD studentship is to gain new insight into human-specific inflammatory responses within the skin through the development of a novel immune-responsive organotypic model. The project will construct and validate a two-compartment model consisting of a 3D organotypic skin construct and an immune compartment joined by perfused cell culture medium. The specific objectives include:1. Establish a 3D organotypic model of human skin within a commercially available fluidic platform (Kirkstall Ltd, QV600).2. Characterise immune infiltration and the response of resident skin cells (keratinocytes and fibroblasts) when neutrophils, monocytes or macrophages are perfused through the system.3. Analyse the dynamic responses (migration, proliferation, and differentiation) of immune and resident skin cells to chemical irritants and purified bacterial products applied to the skin surface.4. Investigate the molecular mediators involved in skin-immune system cross-talk within this platform by profiling cytokine release (Luminex) and functional inhibition with RNAi and small molecules.The successful completion of this project will establish a next-generation model of human skin with immune-responsive capability. This platform will be a powerful tool for understanding human-specific skin biology and the testing and development of new compounds and therapeutics. This interdisciplinary studentship will provide advanced training in skin biology, 3D culture models, bioengineering, and immunology. PhD supervision and training will be managed by academics with expertise in each of these fields, and the student will benefit from state-of-the-art facilities within the Blizard. In addition, the student will carry out a 3 month industrial placement at Kirkstall Ltd, a UK-based SME developing fluidic culture systems for a range of different tissue models. Here, the student will gain additional experience in fluidic systems and their applications for different tissue and disease models. The student will further develop transferable skills in product development, commercialisation, communication, and marketing.