Using naturally evolved phenotypic variation to decipher the positional regulatory code of mammalian skin

利用自然进化的表型变异破译哺乳动物皮肤的位置调节密码

• 批准号: 10246985
• 负责人: Ricardo Mallarino
• 金额: $ 39.69万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246985
• 关键词: Anatomy; Biology; Biomedical Research; Code; Cutaneous; Development; Developmental Biology; Discipline; Disease; Embryo; Embryonic Development; Genetic; Genotype; Growth; Homeostasis; Individual; Laboratories; Laboratory mice; Lead; Link; Marsupialia; Membrane; Modeling; Molecular; Molecular Biology; Molecular Genetics; Morphology; Outcome; Pattern; Pattern Formation; Phenotype; Pigmentation physiologic function; Postdoctoral Fellow; Process; Regulator Genes; Research; Rodent; Science; Skin; System; Thick; Translating; Variant; Work; appendage; base; cell behavior; experimental study; functional genomics; genetic information; insight; interdisciplinary approach; post-doctoral training; postnatal; programs; regional difference; skin organogenesis; success; tool

Project summary My proposed research seeks to uncover the precise developmental mechanisms by which gene regulatory complexity is translated through cellular behaviors into specific morphological outcomes. Achieving this constitutes a fundamental challenge in biomedical sciences, as errors in embryonic patterning often lead to congenital and postnatal abnormalities that can have The mammalian skin displays marked anatomical variation in growth, thickness, pigmentation, and types of cutaneous appendages. These regional differences arise during embryogenesis, suggesting that gene regulatory networks controlling skin development harbor a latent reservoir of anatomical complexity. To understand how such regulatory complexity is translated into spatial patterns of cellular differentiation, drastic consequences for individuals. my research program combines the study of diverse, naturally occurring phenotypes in emerging model species, with parallel studies in the laboratory mouse, where powerful molecular and genetic tools already exist. The proposed experiments seek to elucidate how the skin acquires, interprets, and executes positional information by focusing on two distinct spatially patterned phenomena during skin development (1) stripe pattern formation in rodents, using a system I established as a postdoc and (2) formation of gliding membranes in marsupials, using a system under development in my laboratory. The approaches described in the two research programs integrate multiple disciplines, including developmental biology, molecular biology, evolutionary genetics, and functional genomics, with my expertise in skin developmental biology (postdoctoral training) and demonstrated success developing molecular tools in emerging model species (graduate and postdoctoral training). By focusing on developmental mechanisms, this work will uncover the stepwise processes by which genetic information generates spatial patterns of cellular differentiation during embryogenesis, provide a comprehensive roadmap for linking genotype and phenotype at an unprecedented mechanistic and conceptual level, and will generate fundamental insights into the biology of mammalian skin, from the processes controlling skin development and homeostasis to the mechanistic bases of diseased states.

项目摘要 我提出的研究旨在揭示基因的精确发育机制， 调控的复杂性通过细胞行为转化为特定的形态 结果。实现这一目标构成了生物医学科学的一个根本挑战， 在胚胎模式中，通常会导致先天性和出生后的异常， 哺乳动物的皮肤显示出明显的解剖变异 在生长、厚度、色素沉着和皮肤附属物的类型方面。这些区域 差异出现在胚胎发育过程中，这表明基因调控网络控制 皮肤发育隐藏着解剖学复杂性潜在储存库。为了了解这种 调节复杂性被转化为细胞分化的空间模式， 对个人的严重后果。 我的研究 该计划结合了对新兴模型中多种自然发生的表型的研究 物种，在实验室小鼠中进行平行研究，其中强大的分子和遗传 工具已经存在。拟议的实验试图阐明皮肤如何获得， 通过聚焦于两个不同的空间图案， 皮肤发育过程中的现象（1）啮齿动物中的条纹图案形成，使用系统I 建立了一个博士后和（2）形成的滑翔膜在有袋动物，使用系统 在我的实验室里进行。两个研究项目中描述的方法 整合多学科，包括发育生物学，分子生物学，进化生物学， 遗传学和功能基因组学，以及我在皮肤发育生物学方面的专业知识， （博士后培训），并展示了在新兴模型中开发分子工具的成功 物种（研究生和博士后培训）。通过关注发展机制， 这项工作将揭示遗传信息产生空间信息的逐步过程。 胚胎发生过程中的细胞分化模式，提供了全面的路线图， 在前所未有的机制和概念层面上将基因型和表型联系起来， 产生对哺乳动物皮肤生物学的基本见解， 控制皮肤发育和疾病状态的机制基础的体内平衡。