Organ Specific Project

器官特定项目

• 批准号: 10531004
• 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/10531004
• 关键词: 3-Dimensional; Abdomen; Address; Affect; Age; Aging; Apocrine Glands; Architecture; Atlases; Back; Biology of Aging; Biomedical Engineering; Blood Vessels; Cells; Cheek structure; Cicatrix; 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; Lead; 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; Structure; Temperature; Visualization software; appendage; base; cell community; cell type; data integration; exhaustion; 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 人体皮肤及其附属物包括体内最大的器官。除了其障碍功能， 皮肤参与与维持稳态控制有关的任务，例如温度调节，维护 机械结构的完整性和弹性，并作为免疫和其他细胞类型的储层 对防御和伤口修复至关重要。机械研究表明，这些变化已删除 功能源于内在和外在因素的组合。然后这些因素受到 年龄，性别和种族。随着人类的年龄，几乎所有的皮肤功能都受到影响。这些包括结构性损失 完整性和韧性，自我更新能力受损，伤口修复差和疤痕较差，温度差 eccrine汗腺缺陷的调节，雌雄酮产生减少，色素沉着受损和 对环境损害的敏感性，感染和感应增加。这些变化导致 皮肤脆弱性和疾病，表明增加对皮肤了解的需求增加 微环境及其年龄，性别和与种族相关的变化。除了年龄，性别和种族 - 相关的机械结构变化ECM的结构，即皮肤中的细胞生态系统 在整个生命周期内发生了重大变化。在3D皮肤微环境中，ECM结构的变化，细胞 - ECM相互作用，细胞类型/亚群的抽象，其潜在的分子活性/功能基因 对不同人体位置的表达模式和异质性知之甚少。我们建议六个 旨在将正常的，未折扣的皮肤绘制为年龄，种族，性别和体内的位置的功能。 该项目的前两个目的将产生3D参考皮肤的架构图作为 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参考蜂窝图。 建筑映射（AIMS 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，毛发，垂体和eccrine腺体， 血管和神经。目标1-2还将测量皮肤ECM的形态和对齐程度 在3D中。细胞映射（AIMS 3-5）将产生详尽分辨的细胞和分子谱。 毛囊，表皮和真皮，以及大容量的3D“免疫细胞图”，“基质细胞图”和 整个皮肤的“干细胞图”。高内容集成（AIM 6）将生成一个用户友好的软件 提供非专家，具有询问与上下文相关的参考图的能力集成在一起 建筑和蜂窝室。