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.

器官特异性项目总结 人体皮肤及其附属物是人体最大的器官。除了屏障功能外， 皮肤参与与维持稳态控制相关的任务，例如温度调节、维持 机械结构的完整性和弹性，并作为免疫和其他细胞类型的水库， 对防御和伤口修复至关重要机制研究表明，这些有害的变化， 功能源于内在和外在因素的结合。这些因素受到以下因素的影响： 年龄性别种族随着年龄的增长，几乎所有的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，伤口修复和瘢痕形成不良，温度低 调节从不足的外分泌汗腺，减少激素的生产，受损的色素沉着， 易受环境损害，增加炎症和衰老。这些变化导致 皮肤脆弱性和疾病，指出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。除了年龄性别种族 ECM结构的相关机械结构变化，皮肤内的细胞生态系统 在整个生命周期中会发生显著变化。在3D皮肤微环境中，ECM结构、细胞- ECM相互作用、细胞类型/亚群丰度、其潜在分子活性/功能基因 表达模式和不同身体部位的异质性知之甚少。我们建议六个 目的是绘制正常的、未患病的皮肤作为年龄、种族、性别和身体位置的函数。 该项目的前两个目标将产生皮肤的3D参考建筑图， 年龄，性别，种族和皮肤位置，而接下来的三个目标将产生相关的3D参考细胞图。 架构映射（目标1-2）将评估3D分子组成和形态/拓扑结构的 皮肤的主要多细胞结构，包括表皮、真皮、毛囊、顶泌腺和外泌腺， 血管和神经目的1-2还将测量皮肤的ECM的形态和对齐程度 在3D中。细胞定位（目标3-5）将产生详尽的空间分辨的细胞和分子谱， 毛囊、表皮和真皮，以及大体积3D“免疫细胞图谱”、“基质细胞图谱”， 整个皮肤的“干细胞图谱”。高内容集成（目标6）将产生一个用户友好的软件， 为非专家提供询问上下文相关参考地图的能力， 建筑和细胞隔间。