Interdependence of lineages within the mammalian skin

哺乳动物皮肤内谱系的相互依赖性

• 批准号: 9349455
• 负责人: Ya-Chieh Hsu
• 金额: $ 37.18万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-09 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349455
• 关键词: Adipocytes; Adipose tissue; Alpha Cell; Architecture; Area; Atrophic condition of skin; Blood; Cell Communication; Cell physiology; Cells; Communication; Data; Dehydration; Dermal; Dermis; Development; Disease; Effectiveness; Embryo; Epidermis; Epithelial; Exhibits; Fibroblasts; Future; Generations; Genetic; Goals; Growth; Hair follicle structure; Human; Immune; Impaired wound healing; Infection; Infiltration; Investigation; Knock-out; Knowledge; Lead; Maintenance; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Natural regeneration; Organism; Pathologic; Pathway interactions; Pattern; Phase; Phenotype; Physiological; Play; Population; Production; Rest; Resting Phase; SHH gene; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Skin Transplantation; Skin graft; Specificity; Stem cells; System; Testing; Therapeutic; Therapeutic Intervention; Thick; Thinness; Time; Tissues; Treatment Efficacy; Work; Wound Healing; appendage; base; body system; cell type; chemotherapy; experimental study; healing; in vivo; knockout animal; lipid biosynthesis; migration; mutant; novel; overexpression; postnatal; rapid growth; repaired; smoothened signaling pathway

Project Summary A diverse array of cell types in mammalian skin together protects the organisms from insults, infection, and dehydration. Recent studies have begun to elucidate the interdependency of different cell types and the importance of cell-cell communication for the development and maintenance of a fully functional skin. Hair follicles, important appendages of the epidermis, cycle between a growth phase (anagen) and a rest phase (telogen). Hair follicle cells are not the only cell type that is different between an anagen and a telogen skin: upon anagen entry, the dermis increases significantly through proliferation of dermal fibroblasts embryonically and expansion of the dermal adipose layer postnatally, resulting in skin that is thicker and more resilient than telogen skin. Anagen skin also exhibits faster wound-healing than telogen skin. Despite these known differences, however, there remains a fundamental gap in understanding of the signaling pathways and specific cell-cell communications that lead to these changes. This gap poses a significant impediment to effective therapeutic intervention in a variety of areas including wound repair, congenital dermal disorders, and atrophic skin following chemotherapy or skin grafting. Transit-amplifying cells (TACs) are generated by long- term stem cells as an intermediate population that produce downstream progeny. Hair follicle TACs (HF-TACs) are an anagen-specific population. Our preliminary data indicate that HF-TACs play a key role in these anagen-specific skin changes through a mechanism involving Sonic Hedgehog (SHH). The overall objective of this proposal is to elucidate the cellular mechanisms by which HF-TAC-specific SHH mediates anagen-specific skin changes and to identify the signal-receiving cells that are responsible for dermal thickening and faster wound healing in anagen skin. Our central hypothesis is that the SHH signaling, operating through the key downstream mediator, Smoothened, orchestrates the changes that make anagen skin thicker, more resilient, and faster healing. To test this hypothesis rigorously, a systematic in vivo approach will be taken to examine the direct requirement of SHH signaling in different cell types in the skin by knocking-out essential downstream mediators of SHH and comparing the phenotypes of these mutants to phenotypes of Shh knockout skin. The cell types to be examined include hair follicles, dermal fibroblasts, mature adipocytes, and adipocyte precursors. We will use cell-type specific inducible or constitutive Cre lines that we have verified extensively for expression patterns and effectiveness. We expect that the experiments outlined in this proposal will elucidate a physiologically relevant pathway by which anagen skin becomes thicker and heals better. We anticipate that the knowledge gained will identify critical cell types and/or signals that might be harnessed therapeutically in pathological conditions. The results may also identify novel regulatory functions exerted by TACs on the surrounding microenvironment, which would likely impact studies of TACs in other systems.

项目摘要 哺乳动物皮肤中的多种细胞类型共同保护生物体免受损伤、感染和感染。 脱水最近的研究已经开始阐明不同细胞类型的相互依赖性， 细胞间通讯对于发育和维持功能齐全的皮肤的重要性。头发 毛囊是表皮的重要附属物，在生长期（生长期）和静止期之间循环 （休止期）。毛囊细胞不是生长期和休止期皮肤之间唯一不同的细胞类型： 在进入生长期时，真皮通过真皮成纤维细胞的胚胎性增殖而显著增加， 以及出生后真皮脂肪层的扩张，导致皮肤比其他皮肤更厚，更有弹性。 静止期皮肤生长期皮肤也比静止期皮肤表现出更快的伤口愈合。尽管这些已知的 然而，在对信号通路的理解方面仍然存在根本性的差距， 导致这些变化的特定细胞间通讯。这一差距严重阻碍了 在各种领域进行有效的治疗干预，包括伤口修复、先天性皮肤疾病， 化疗或植皮后皮肤萎缩。转运放大细胞（TAC）是由长- 术语干细胞作为产生下游后代的中间群体。毛囊TAC（HF-TAC） 是一个特定的种群。我们的初步数据表明，HF-TACs在这些过程中起着关键作用。 再生期特异性皮肤通过涉及Sonic Hedgehog（SHH）的机制发生变化。的总体目标 该建议旨在阐明HF-TAC特异性SHH介导抗原特异性 皮肤的变化，并确定负责真皮增厚和更快的信号接收细胞， 在生长期皮肤的伤口愈合。我们的中心假设是，SHH信号，通过关键 下游介质，平滑，协调的变化，使生长期皮肤更厚，更有弹性， 更快的愈合。为了严格检验这一假设，将采取系统的体内方法来检查 通过敲除皮肤中不同细胞类型中的必需下游SHH信号传导的直接需求 SHH的介导物，并将这些突变体的表型与Shh敲除皮肤的表型进行比较。的 待检查的细胞类型包括毛囊、真皮成纤维细胞、成熟脂肪细胞和脂肪细胞 前体我们将使用我们已经广泛验证的细胞类型特异性诱导型或组成型Cre系 表达模式和有效性。我们希望本提案中概述的实验将阐明 生理相关的途径，通过该途径，生长期皮肤变得更厚并且愈合得更好。我们预计 所获得的知识将确定关键的细胞类型和/或信号， 病理条件。这些结果也可以确定新的调控功能发挥的总抗肿瘤细胞对 周围的微环境，这可能会影响其他系统中的TAC研究。