Organ Specific Project

器官特定项目

• 批准号: 10708880
• 负责人: Denis Wirtz
• 金额: $ 25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708880
• 关键词: 3-Dimensional; Abdomen; Address; Affect; Age; Aging; Apocrine Glands; Architecture; Atlases; Back; Biology of Aging; Biomedical Engineering; Blood Vessels; Cells; Cellular Structures; Cheek structure; Cicatrix; Classification; Communication; Dermal; Dermatopathology; Dermis; Disease; Dorsal; Eccrine Glands; Ecosystem; Epidermis; Epigenetic Process; Extracellular Matrix; Gene Expression Profile; Genetic Transcription; Hair follicle structure; Hand; Heterogeneity; Hormonal; Hormones; Human; Immune; Impairment; Individual; Inflammation; Location; Longevity; Maps; Measures; Medicine; Molecular; Molecular Profiling; Morphology; Nerve; Organ; Pattern; Pigmentation physiologic function; Predisposition; Production; Race; Regulation; Resolution; Role; Scalp structure; Skin; Skin Tissue; Stromal Cells; Temperature; Visualization software; appendage; cell community; cell type; data integration; multiple omics; resilience; self-renewal; senescence; sex; statistics; stem; stem cells; technology development; user friendly software; user-friendly; wound healing

Summary, Organ Specific Project Human skin and its appendages comprise the largest organ in the body. In addition to its barrier function, the skin is involved in tasks related to maintaining homeostatic control such as temperature regulation, maintaining mechano-structural integrity and resilience, and serving as a reservoir for immune and other cell types that are critical for defense and wound repair. Mechanistic studies have shown that deleterious changes to these functions stem from combinations of both intrinsic and extrinsic factors. These factors are then influenced by age, sex, and race. As humans age, nearly all skin functions are affected. These include the loss of structural integrity and resilience, impaired self-renewal capabilities, poor wound repair and scarring, poor temperature regulation from deficiencies in eccrine sweat glands, decreased hormone production, impaired pigmentation and susceptibility to environmental damage, and increased inflammation and senescence. These changes lead to skin fragility and disease, pointing to the increased need for enhanced understanding of the skin microenvironment and its age-, sex-, and race-associated changes. In addition to the age-, sex-, and race- associated mechano-structural changes to the architecture of the ECM, the cellular ecosystem within the skin changes significantly over the lifespan. Within the 3D skin microenvironment, changes in ECM architecture, cell- ECM interactions, abundance of cell types/subpopulations, their underlying molecular activity/functional gene expression patterns, and heterogeneity across different body locations are poorly understood. We propose six Aims to map the normal, non-diseased skin as a function of age, race, sex, and location on the body. The first two Aims of the Project will produce 3D reference architectural maps of skin as a function of age, sex, race, and skin location, while the next three Aims will produce associated 3D reference cellular maps. Architectural mapping (Aims 1-2) will assess the 3D molecular composition and morphology/topology of the major multi-cellular structures of skin, including epidermis, dermis, hair follicles, apocrine and eccrine glands, blood vessels, and nerves. Aims 1-2 will also measure morphology and degree of alignment of the ECM of skin in 3D. Cellular mapping (Aims 3-5) will produce exhaustive spatially resolved cellular and molecular profiles of hair follicles, epidermis, and dermis, as well as large-volume 3D “immune cell maps”, “stromal cell maps”, and “stem cell maps” of the entire skin. High-content integration (Aim 6) will produce a user-friendly software that provides non-experts with the ability to interrogate context-dependent reference maps integrating both architectural and cellular compartments.

摘要，器官特定项目 人类皮肤及其附属器构成了体内最大的器官。除了其屏障功能外， 皮肤参与与维持体内平衡控制相关的任务，例如温度调节、维持 机械结构完整性和弹性，并作为免疫细胞和其他细胞类型的储存库 对于防御和伤口修复至关重要。机制研究表明，这些有害的变化 功能源于内在因素和外在因素的结合。这些因素随后受到影响 年龄、性别和种族。随着人类年龄的增长，几乎所有皮肤功能都会受到影响。其中包括结构性损失 完整性和弹性、自我更新能力受损、伤口修复和结疤不良、温度差 调节小汗腺缺陷、激素产生减少、色素沉着受损和 容易受到环境损害，并增加炎症和衰老。 These changes lead to 皮肤脆弱性和疾病，表明人们越来越需要加强对皮肤的了解 微环境及其与年龄、性别和种族相关的变化。除了年龄、性别和种族之外 与 ECM 结构（皮肤内的细胞生态系统）相关的机械结构变化 在生命周期内发生显着变化。在 3D 皮肤微环境中，ECM 结构、细胞- ECM 相互作用、细胞类型/亚群的丰度、其潜在的分子活性/功能基因 人们对不同身体部位的表达模式和异质性知之甚少。我们建议六 旨在根据年龄、种族、性别和身体位置绘制正常、无病皮肤的图。 该项目的前两个目标将生成皮肤的 3D 参考建筑图，作为以下函数： 年龄、性别、种族和皮肤位置，而接下来的三个目标将生成相关的 3D 参考细胞图。 架构测绘（目标 1-2）将评估 3D 分子组成和形态/拓扑 皮肤的主要多细胞结构，包括表皮、真皮、毛囊、顶浆腺和小汗腺， 血管、神经。目标 1-2 还将测量皮肤 ECM 的形态和排列程度 在 3D 中。细胞作图（目标 3-5）将产生详尽的空间分辨细胞和分子特征 毛囊、表皮、真皮，以及大容量3D“免疫细胞图”、“基质细胞图”等 整个皮肤的“干细胞图”。高内容集成（目标 6）将产生一个用户友好的软件， 为非专家提供了询问上下文相关参考图的能力，集成了两者 建筑和细胞隔室。