Interdependence of lineages within the mammalian skin

哺乳动物皮肤内谱系的相互依赖性

基本信息

批准号：
9755354
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
项目类别：
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/9755354
关键词：
Adipocytes Adipose tissue 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

项目摘要

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.

项目概要哺乳动物皮肤中的多种细胞类型共同保护生物体免受侮辱、感染和脱水。最近的研究已经开始阐明不同细胞类型的相互依赖性和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，表皮的重要附属物，生长期（生长期）和休止期之间的循环（休止期）。毛囊细胞并不是生长期和休止期皮肤之间唯一不同的细胞类型：进入生长期后，真皮通过胚胎期真皮成纤维细胞的增殖而显着增大以及出生后真皮脂肪层的扩张，导致皮肤比以前更厚、更有弹性休止期皮肤。生长期皮肤还表现出比休止期皮肤更快的伤口愈合。尽管有这些已知的然而，对信号通路和信号通路的理解仍然存在根本差距。导致这些变化的特定细胞间通讯。这一差距对在伤口修复、先天性皮肤疾病等多个领域进行有效的治疗干预化疗或植皮后皮肤萎缩。过渡放大细胞（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) 是生长期特定的群体。我们的初步数据表明 HF-TAC 在这些方面发挥着关键作用生长期特异性皮肤通过涉及 Sonic Hedgehog (SHH) 的机制发生变化。总体目标该提案旨在阐明 HF-TAC 特异性 SHH 介导生长期特异性的细胞机制皮肤变化并识别导致真皮增厚和加速的信号接收细胞毛发生长初期皮肤的伤口愈合。我们的中心假设是 SHH 信号通过关键的操作下游介质，Smoothened，协调变化，使生长期皮肤更厚，更有弹性，和更快的愈合。为了严格检验这一假设，将采用系统的体内方法来检验通过敲除必需的下游，满足皮肤不同细胞类型中 SHH 信号传导的直接需求 SHH 介质，并将这些突变体的表型与 Shh 敲除皮肤的表型进行比较。这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。我们将使用经过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。我们期望本提案中概述的实验将阐明生长期皮肤变得更厚并且愈合得更好的生理相关途径。我们预计获得的知识将识别可用于治疗的关键细胞类型和/或信号病理状况。结果还可能确定 TAC 对周围的微环境，这可能会影响其他系统中 TAC 的研究。