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

项目摘要 老龄化是一个日益紧迫的公共卫生问题，在很大程度上是因为它伴随着更高的 与年龄有关的慢性疾病的发生率。老化是自然发生的，随着时间的推移（在重复 细胞复制）并且受许多环境因素的影响。人类的皮肤和其他组织一样 在个体的生命周期中经历一个内在的老化过程，称为时间老化。此外，本发明还 皮肤持续暴露于环境因素，例如紫外线辐射（UVR），其被认为是 是许多皮肤癌和加速皮肤老化（称为光老化）发展的主要危险因素， 其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- 衰老黑素细胞、角质形成细胞和成纤维细胞的相关积累能够表达 衰老相关分泌表型（SASP），通过复杂的网络促进炎症 自分泌和旁分泌强化，改变组织微环境，并具有深刻的有害作用。 影响皮肤结构和完整性。因此，有必要确定主要皮肤的特征- 经历衰老的驻留细胞类型，以及它们在衰老过程中表达的个体SASP谱， 在皮肤微环境的建立中发挥作用的时间性和外在诱导的衰老 容易导致年龄相关的疾病我们的实验室已经开发出复杂的3D皮肤模型， 在体外微流体平台内的正常皮肤生理学，其可以与模块化的其他器官组合， 组织芯片平台。在微流体平台中培养的3D工程组织是 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，其中包含用于映射组织中衰老细胞的关键生物变量， 并且将包括：1）两种性别; 2）皮肤色素沉着光型的全范围;以及3）年龄范围 人类的寿命我们的皮肤微流控平台，结合了创新技术，如空间 转录组学是研究皮肤衰老机制的有力工具 和新的方法来恢复与年龄有关的条件。这项提议将立即和无缝 整合到最近成立的CUSTMAP中心在哥伦比亚大学，这是一个创始 SenNet联盟的组织映射中心。微流体组织模型可以定制用于许多应用。 在SenNet上代表的组织，能够生成广泛的芯片上衰老 财团的平台。

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.