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.

项目概要 老龄化是一个日益突出的公共卫生问题，很大程度上是因为它伴随着更高的 与年龄相关的慢性疾病的频率。衰老是随着时间的推移而自然发生的（经过反复 细胞复制）并受到许多环境因素的影响。人类的皮肤和所有其他组织一样， 在个体的一生中经历一个内在的衰老过程，称为时间老化。此外， 皮肤不断暴露在环境因素中，例如紫外线辐射（UVR），这被认为是 导致许多皮肤癌和加速皮肤老化（称为光老化）的主要危险因素， 这与色素沉着过度和加速黑色素瘤形成有关。在皮肤里，有一个年龄—— 相关的衰老黑素细胞、角质细胞和成纤维细胞的积累，这些细胞能够表达 衰老相关分泌表型（SASP），通过复杂的网络促进炎症 自体和旁分泌的强化可以改变组织微环境，并具有深远的有害作用 对皮肤结构和完整性的影响。因此，有必要确定主要皮肤的特征 正在经历衰老的常驻细胞类型，以及它们在衰老过程中表达的个体 SASP 谱 时间顺序和外在诱发的衰老在皮肤微环境的建立中发挥作用 有利于与年龄有关的疾病。我们的实验室开发了复杂的 3D 皮肤模型，概括了 体外微流体平台内的正常皮肤生理学，可以与模块化的其他器官结合 组织芯片平台。在微流体平台中培养的 3D 工程组织是强大的工具 在受控环境中重现生理条件并研究生理现象。我们 将生成 3D 皮肤模型，其中包含用于绘制组织中衰老细胞的关键生物变量， 并将包括： 1) 男女； 2）全系列皮肤色素沉着照型； 3）年龄范围 人类的寿命。我们的皮肤微流体平台结合了空间等创新技术 转录组学是研究导致皮肤衰老机制的强大新工具 以及恢复与年龄相关的状况的新方法。该提案将立即、无缝地 融入哥伦比亚大学最近成立的 CUSTMAP 中心，该中心是该中心的创始机构之一 SenNet 联盟的组织作图中心。微流控组织模型可以针对许多领域进行定制 SenNet 中代表的组织，能够生成各种衰老芯片 为联盟提供平台。