Senescence-on-a-chip: Building a microphysiological 3D skin model

芯片衰老：构建微生理 3D 皮肤模型

• 批准号: 10685382
• 负责人: Angela M Christiano
• 金额: $ 55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10685382
• 关键词: 3-Dimensional; Acceleration; Adopted; Affect; Age; Aging; Asthma; Atopic Dermatitis; Biological; Bystander Effect; Cardiovascular Diseases; Cell Aging; Cell Culture Techniques; Cells; Characteristics; Chronic; Chronology; Complex; Controlled Environment; Data; Dermal; Dermis; Development; Disease; Distant; Environment; Environmental Risk Factor; Epidermis; Evaluation; Exposure to; Fibroblasts; Freezing; Frequencies; Gender; Generations; Genes; Goals; Heart; Histologic; Human; Hyperpigmentation; In Vitro; Individual; Inflammation; Joints; Kidney; Libraries; Longevity; Lung; Lupus; Maps; Mediating; Microfluidics; Modeling; Muscle; Organ; Paracrine Communication; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Play; Process; Protocols documentation; Psoriasis; Psoriatic Arthritis; Psychological reinforcement; Public Health; Risk Factors; Role; Skin; Skin Aging; Skin Cancer; Skin Physiology; Skin Pigmentation; Skin Tissue; Structure; Techniques; Testing; Time; Tissue Engineering; Tissue Model; Tissues; Ultraviolet Rays; Universities; Vascular Endothelial Cell; age group; age related; analytical tool; bioprinting; cell type; cytokine; efficacy evaluation; experimental study; innovation; keratinocyte; melanocyte; melanoma; metabolomics; multiple omics; multiplex assay; novel drug class; novel strategies; paracrine; senescence; sex; skin disorder; tissue culture; tissue mapping; tool; transcriptomics

PROJECT SUMMARY Aging is an increasingly emergent public health issue, in large part because it is accompanied by a higher frequency of chronic age-related diseases. Aging occurs naturally as a consequence of time (upon repeated cellular replication) and is influenced by a number of environmental factors. Human skin, like all other tissues, undergoes an intrinsic aging process during an individual’s lifespan known as chronological aging. Additionally, the skin is constantly exposed to environmental factors such as UV radiation (UVR), which is recognized as the major risk factor for the development of many skin cancers and accelerated skin aging, known as photoaging, which is associated with hyperpigmentation and accelerated melanoma formation. In the skin, there is an age- associated accumulation of senescent melanocytes, keratinocytes and fibroblasts capable of expressing the senescence-associated secretory phenotype (SASP), which promotes inflammation through a complex network of auto- and paracrine reinforcement that modifies the tissue microenvironment and has a profound deleterious effect on skin structure and integrity. Thus, it is necessary to determine the characteristics of the major skin- resident cell types undergoing senescence, as well as their individual SASP profiles expressed during chronological and extrinsically-induced aging that play a role in the establishment of a skin microenvironment conducive to age-related disorders. Our lab has developed sophisticated 3D skin models that recapitulate normal skin physiology within a microfluidic platform in vitro, which can combined with other organs in a modular tissue-on-a-chip platform. 3D engineered tissues cultured in microfluidic platforms are powerful tools to recapitulate physiological conditions and investigate physiological phenomena in a controlled environment. We will generate 3D skin models that encompass critical biological variables for mapping senescent cells in tissues, and will encompass: 1) both genders; 2) the full range of skin pigmentation phototypes; and 3) age ranges across the human lifespan. Our skin microfluidic platform, combined with innovative techniques such as spatial transcriptomics, represents a powerful new tool to investigate the mechanisms leading to senescence in the skin and new approaches to revert age-related conditions. This proposal will have immediate and seamless integration into the recently established CUSTMAP Center at Columbia University, which is one of the founding Tissue Mapping Centers of the SenNet consortium. Microfluidic tissue models can be customized for many of the tissues represented across the SenNet, enabling the generation of a wide range of senescence-on-a-chip platforms for the Consortium.

项目摘要 衰老是一个日益紧急的公共卫生问题，在很大程度上是因为它伴随着更高的 慢性年龄相关疾病的频率。衰老是由于时间而自然发生的（重复时） 细胞复制），受许多环境因素的影响。像所有其他时间一样，人类皮肤 在个人的寿命中，经历了固有的衰老过程，称为年代老化。此外， 皮肤不断暴露于环境因素（例如UV辐射（UVR）），该因素被认为是 许多皮肤癌和加速皮肤老化的主要危险因素，称为光照， 在皮肤中，有一个年龄 - 感官黑素细胞，角质形成细胞和成纤维细胞的相关积累能够表达 感应相关的秘书表型（SASP），该表型通过复杂网络促进注射 修饰组织微环境的自动和旁分泌加固，具有深刻的有害状态 对皮肤结构和完整性的影响。这是有必要确定主要皮肤的特征 居民细胞类型正在感受，以及在其在 按年代和外在引起的衰老，在制定皮肤微环境中发挥作用 导电到与年龄有关的疾病。我们的实验室开发了复杂的3D皮肤模型，可以概括 体外微流体平台内的正常皮肤生理学，该平台可以与模块化中的其他器官结合 片上的组织平台。在微流体平台上培养的3D工程组织是强大的工具 概括生理条件并研究受控环境中的生理现象。我们 将产生3D皮肤模型，该模型包含关键的生物学变量，以绘制组织中的感官细胞， 并将包括：1）两个性别； 2）全范围的皮肤色素沉着光型； 3）年龄范围 人类的寿命。我们的皮肤微流体平台，结合创新技术，例如空间 转录组学代表了研究导致皮肤感受的机制的强大新工具 以及恢复与年龄相关的条件的新方法。该建议将立即无缝 集成到最近成立的哥伦比亚大学的Custmap中心，这是创始人之一 Sennet联盟的组织映射中心。微流体组织模型可以针对许多 在sennet上代表的组织，可以在片上产生广泛的衰老 财团的平台。