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

项目摘要/摘要皮肤附属物，包括牙齿，头发，eccerine和乳腺网格，是明显的，医学上的人类整数的特征。先天性和后附属物的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，但经常使人衰弱。有许多具有皮肤附属物疾病的基因座，将遗传病变与人联系起来的分子病因在许多情况下，表型仍然晦涩难懂。了解调节皮肤的分子机制实验模型系统中的吊坠模式和形态发生为开发的新途径提供了新的途径皮肤病的疗法。确实，对鸡和鼠标模型系统的研究已大大提高了我们的了解皮肤附属物发育的遗传调节，并已经影响了临床皮肤科。重要的是，模式提示，形态发生细胞行为和调节机制将它们链接在斑马鱼附属物的开发中是保守的。因为皮肤附属于超级官方 - 在发育中的透明皮肤中，研究斑马鱼的皮肤图案和形态发生可以使当前在其他模型系统中无法进行分辨率的细胞和分子动力学的体内分析。 AIM 1中的研究将有助于我们理解皮肤的正确分布如何通过利用实时成像和有条件遗传学来测试新型迁徙人群的作用，实现皮肤细胞可能调节皮肤附属模式。这些研究也将在第一次发现控制完整脊椎动物皮肤皮肤细胞迁移的分子机制。 AIM 2的研究将使日期机制应对已知的信号传导蛋白的动态空间分布是必不可少的早期皮肤附属物形态发生过程中的上皮 - 间质相互作用。通过使用调节在遗传性外胚层的斑马鱼模型中重建信号网络的状态转化表达式发育不良，这些实验将揭示有关上皮 - 间质信号相互作用的机制在分子分辨率下。这些研究将共同解决一些最重要的未解决问题关于皮肤附属物发育并提供潜在的潜在道路以了解分子病因影响这些组织的人类疾病。 1