Modeling of human HSV infection: development of immune-competent 3D skin-on-chip with vascular perfusion

人类 HSV 感染建模：开发具有血管灌注功能的免疫活性 3D 皮肤芯片

基本信息

批准号：
10328978
负责人：
Jia Zhu
金额：
$ 53.35万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328978
关键词：
3-Dimensional Adult Affect Animal Model Antigenic Diversity Antigenic Specificity Antiviral Response Architecture Autologous Biological Biological Models Biomedical Engineering Biomimetics Biopsy Blood Blood Vessels Blood Volume CD8-Positive T-Lymphocytes CD8B1 gene Cell Compartmentation Cell Culture System Cell Density Cell model Cells Clinical Trials Communicable Diseases Complex Containment Dermis Development Devices Disease Disease model Elements Endothelium Engineering Epidermis Event Failure Fibroblasts Fluorescent in Situ Hybridization Functional disorder Gene Expression Profiling Genital Genitalia Goals Health Herpes Simplex Virus Vaccines Herpesviridae Infections Herpesvirus 1 Homing Host Defense Human Human Herpesvirus 2 Human body Immune Immune response Immunity Immunocompetent Immunologic Surveillance Immunologics In Vitro Individual Infection Infectious Skin Diseases Investigation Kinetics Knowledge Lesion Life Mediating Medical Memory Microfluidic Microchips Modeling Molecular Mucous Membrane Mus Oral Organ Organ Model Patients Penetration Perfusion Pharmacology Phase Phase III Clinical Trials Physiological Population Preclinical Testing Predictive Value Predisposition Prevalence Process Signal Pathway Simplexvirus Skin Skin Tissue Structure Surface System T memory cell T-Lymphocyte Therapeutic Therapeutic Agents Time Tissue Model Tissues Topical application Ulcer Vaccines Vascularization Viral Virus Virus Diseases chemokine cost data modeling drug candidate drug development drug efficacy efficacy testing genetic signature genital herpes human disease human model human tissue immune activation in vitro Model in vivo innovation insight keratinocyte medication safety model design model development pathogen research and development response skin disorder subcutaneous

项目摘要

SUMMARY Conventional mechanistic research and drug development relies heavily on in vivo animal models and in vitro cell culture systems. Although conventional in vitro cultured 2D or 3D cells enable the analysis of signaling pathways and the identification of signature genes associated with responses of infection or various conditions and treatments, they can't reproduce complex cell-cell and cell-matrix interactions occurring in the tissue microenvironment. Animal models provide understanding on in vivo integrated multi-organ responses but serious concerns exist over their predictive value and biological relevance to humans. In fact, more and more drug candidates have failed to advance from Phase I to Phase III clinical trials and to reach the market. Critical challenges to reduce costly failures in clinical trials highlight the urgency to generate better model systems for preclinical testing of drug efficacy and safety in humans, and for understanding molecular mechanisms underlying thousands of human diseases. A three-dimensional (3D) human tissue model promises compelling advantages to predict complex physiological functions, immune responses to infectious diseases, and pharmacological responses to therapeutic agents. Such a synthetic tissue model has outstanding potential for reliable drug efficacy testing and as a superior replacement for an animal model, especially for those infectious diseases that do not have adequate animal models. Skin is the largest organ of the human body and forms a barrier to protect the body against pathogens and penetration of potential harmful substances. In order to mimic the organ-level skin pathophysiology in humans, we propose to harness bioengineering approaches to develop an in vitro 3D `skin-on-chip' that incorporates circulating immune cells into the normal architecture of skin epidermis and dermis for modeling of viral-host interactions in human herpes simplex virus (HSV) infection. Our Specific Aims are: 1) Establish and validate a vascularized 3D `skin-on-chip' platform using donor-derived primary cells for modeling of HSV infection and identifying key immune responses for protection. 2) Recapitulate a tissue resident memory T-cell compartment in 3D vascularized `skin-on-chip' for modeling of antigenic specificity, cell density and TCR diversity in tissue resident memory T-cell mediated local immune protection.

概括常规的机械研究和药物开发在很大程度上取决于体内动物模型和体外细胞培养系统。尽管常规的体外培养的2D或3D细胞能够分析信号途径和与感染反应相关的签名基因的鉴定和治疗方法，他们无法再现在组织中发生的复杂细胞 - 细胞和细胞 - 矩阵相互作用微环境。动物模型提供了对体内综合多器官响应的理解，但对他们与人类的预测价值和生物学相关性存在严重的关注。实际上，越来越多候选毒品未能从I期到III期临床试验，并无法进入市场。批判的减少临床试验中昂贵失败的挑战突出了为生成更好模型系统的紧迫性对人类药物疗效和安全性的临床前测试，以及了解分子机制基本的数千种人类疾病。三维（3D）人体组织模型有望引人注目预测复杂的生理功能，对感染性疾病的免疫反应以及药理学对治疗剂的反应。这样的合成组织模型具有出色的潜力可靠的药物疗效测试，并作为动物模型的优越替代品，特别是对于那些感染力没有足够动物模型的疾病。皮肤是人体最大的器官，形成保护身体免受病原体和潜在有害物质的渗透的障碍。为了模仿人类的器官水平的皮肤病理生理学，我们建议利用生物工程方法开发体外3D“片上皮肤”，将循环的免疫细胞纳入正常结构皮肤表皮和真皮，用于建模人类单纯疱疹病毒（HSV）中的病毒宿主相互作用感染。我们的具体目的是：1）使用并验证使用血管化的3D 3D“皮肤芯片”平台用于建模HSV感染并识别保护的关键免疫反应的供体衍生的原代细胞。 2）在3D血管化的“片上皮肤”中概括组织驻留记忆T细胞室用于建模组织驻留记忆中的抗原特异性，细胞密度和TCR多样性T细胞介导的局部免疫保护。