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。

• 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
• 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

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

项目摘要/摘要 皮肤附属物，包括牙齿、毛发、外分泌腺和乳腺，是明显的，医学上重要的- 人类皮肤的特征。先天性和后天性皮肤附件疾病是常见的 和经常使人衰弱的状况。虽然人类基因分析和临床皮肤病学有关联， 许多位点与皮肤附件疾病，分子病因学连接的遗传病变，以人类 在许多情况下，表型仍然不清楚。了解调节皮肤AP的分子机制- 实验模型系统中的悬垂模式和形态发生为开发 治疗皮肤病。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。 了解皮肤附件发育的遗传调控，并已影响临床 皮肤科。重要的是，图案线索，形态发生细胞行为和调节机制， 连接它们在斑马鱼皮肤附属器发育中是保守的。因为皮肤附属物形成了表层- 斑马鱼的皮肤是透明的，研究斑马鱼的皮肤图案和形态发生， 以目前在其他模型系统中不可能的分辨率进行细胞和分子动力学的体内分析。 目标1中的研究将有助于我们理解皮肤附件的正确分布是如何 通过利用实时成像和条件遗传学来测试一个新的迁移人口的作用， 真皮细胞可能调节皮肤附属物图案。这些研究还将首次揭示， 在完整的脊椎动物皮肤中控制真皮细胞迁移的分子机制。目标2的研究将阐明- 已知调节信号蛋白动态空间分布的机制对于 人类早期皮肤附属器形态发生过程中的上皮-间充质相互作用。通过使用条件- 在遗传性外胚层的斑马鱼模型中通过功能性转基因表达重建信号网络 这些实验将揭示上皮间质信号相互作用的机制 在分子分辨率上。总之，这些研究将解决一些最重要的悬而未决的问题 关于皮肤附件的发展，并提供潜在的进展，以了解分子病因学 影响这些组织的人类疾病。 1