Mechanisms of signal transmission in vertebrate skin appendage development.

脊椎动物皮肤附属器发育中的信号传递机制。

基本信息

批准号：
10414871
负责人：
DAVID M PARICHY
金额：
$ 35.17万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414871
关键词：
Address Affect Animals Attention Basement membrane Biological Assay Biological Models Biology Birds Cells Chicken Model Clinical Complex Coupled Cues Dermal Dermatology Dermis Development Diffusion Disease Eccrine Glands Ectodermal Dysplasia Embryonic Development Epidermis Epithelial Etiology Event Experimental Models Feathers Fertilization Fishes Foundations Genetic Gland Hair Health Heritability Human Human Genetics Image Individual Infrastructure Inherited Integumentary system Lesion Ligands Link Mammals Mammary gland Mediating Medical Mesenchymal Methods Modality Modeling Molecular Morphogenesis Mosaicism Organ Output Pathway interactions Pattern Personal Satisfaction Pharmacology Phenotype Reaction Regenerative Medicine Regulation Research Resolution Role Signal Induction Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Skin Spatial Distribution System Testing Time Tissues Tooth structure Vertebrates WNT Signaling Pathway Work Zebrafish antagonist appendage cell behavior cell motility experimental study extracellular gene product genetic analysis genetic manipulation in vivo in vivo imaging inhibitor insight migratory population molecular dynamics mouse model novel skin disorder skin fibrosis skin organogenesis teleost fish therapy design therapy development transgene expression transmission process wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Skin appendages, including teeth, hair, eccrine and mammary glands, are conspicuous and medically impor- tant features of the human integument. Congenital and acquired disorders of skin appendages are common and frequently debilitating conditions. Although human genetic analyses and clinical dermatology have associ- ated numerous loci with skin appendage disorders, the molecular etiologies linking genetic lesions to human phenotypes in many cases remain obscure. Understanding molecular mechanisms that regulate skin ap- pendage patterning and morphogenesis in experimental model systems provides new avenues for developing therapies for skin disease. Indeed, research on chicken and mouse model systems has greatly advanced our understanding of the genetic regulation of skin appendage development and has already impacted clinical dermatology. Importantly, patterning cues, morphogenetic cell behaviors and the regulatory mechanisms that link them are conserved in zebraﬁsh skin appendage development. Because skin appendages form superﬁcial- ly in the transparent skin of developing ﬁsh, studying zebraﬁsh skin patterning and morphogenesis enables in vivo analysis of cellular and molecular dynamics at resolutions not currently possible in other model systems. Studies in Aim 1 will contribute to our understanding of how the correct distribution of skin appendages is achieved by leveraging live imaging and conditional genetics to test the role of a novel population of migratory dermal cells likely to regulate skin appendage patterning. These studies will also uncover, for the ﬁrst time, molecular mechanisms that govern dermal cell migration in intact vertebrate skin. Studies in Aim 2 will eluci- date mechanisms regulating the dynamic spatial distribution of signaling proteins known to be necessary for epithelial–mesenchymal interactions during early skin appendage morphogenesis in humans. By using condi- tional transgene expression to re-construct signaling networks in a zebraﬁsh model of hereditary ectodermal dysplasia, these experiments will reveal mechanisms governing epithelial–mesenchymal signaling interactions at molecular resolution. Together, these studies will address some of the most important unanswered questions regarding skin appendage development and provide potential inroads to understanding the molecular etiology of human disorders affecting these tissues. 1

项目概要/摘要皮肤附属器，包括牙齿、头发、小汗腺和乳腺，非常显眼且具有医学重要性。人类外皮的特征皮肤附属器的先天性和获得性疾病很常见。尽管人类遗传分析和临床皮肤病学具有相关性。吃了许多与皮肤附属器疾病有关的基因座，将遗传病变与人类联系起来的分子病因学在许多情况下，人们对调节皮肤反应的分子机制仍不清楚。实验模型系统中的悬垂图案和形态发生为开发提供了新途径事实上，对鸡和小鼠模型系统的研究极大地推进了我们的研究。对皮肤附属器发育的基因调控的了解并已对临床产生影响重要的是，模式线索、形态发生细胞行为和调节机制。链接它们在斑马鱼皮肤附属物发育中是保守的，因为皮肤附属物形成表面- 在发育中的鱼类的透明皮肤中，研究斑马鱼皮肤的图案和形态发生能够以目前其他模型系统不可能的分辨率对细胞和分子动力学进行体内分析。目标 1 的研究将有助于我们了解皮肤附属器的正确分布方式通过利用实时成像和条件遗传学来测试新的迁徙种群的作用来实现这些研究还将首次揭示可能调节皮肤附属器图案的真皮细胞。目标 2 中的研究将阐明控制完整脊椎动物皮肤中真皮细胞迁移的分子机制。调节信号蛋白动态空间分布的日期机制已知是必需的人类早期皮肤附属器形态发生过程中的上皮-间质相互作用。转基因表达在遗传性外胚层斑马鱼模型中重建信号网络发育不良，这些实验将揭示控制上皮间质信号相互作用的机制这些研究将共同解决一些最重要的尚未解答的问题。关于皮肤附属器发育并为理解分子病因学提供潜在的进展影响这些组织的人类疾病。 1