Phenotypic Specification in Skin Organogenesis

皮肤器官发生的表型规范

• 批准号: 9068772
• 负责人: Cheng-Ming Chuong
• 金额: $ 57.85万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068772
• 关键词: Adipose tissue; Adult; Aging; Alopecia; Animal Model; Architecture; Artificial skin; Biology; Body Regions; Cells; Characteristics; Chickens; Complex; Coupled; Cutaneous; Data; Dermal; Development; Distal; Employee Strikes; Ensure; Environment; Epigenetic Process; Extracellular Matrix; Face; Feathers; Fibroblast Growth Factor; Funding; Genes; Goals; Grant; Growth; Hair; Health; Homeostasis; Hormones; Human; Image; Individual; Laboratories; Learning; Length; Life; Matrix Metalloproteinases; Mediating; Medical; Modeling; Modification; Molecular; Morphology; Mus; Natural regeneration; Newborn Infant; Organ; Pathway interactions; Patients; Phase; Phenotype; Physiological; Population; Procedures; Process; Puberty; Regenerative Medicine; Regulation; Role; Scalp structure; Scientist; Series; Shapes; Signal Transduction; Signaling Molecule; Skin; Specific qualifier value; Specificity; Staging; Stem cells; Technology; Testing; Time; Variant; Width; Work; Wounds and Injuries; appendage; base; epigenetic regulation; face skin; keratinocyte; member; monolayer; progenitor; regenerative; regional difference; self organization; skin organogenesis; skin regeneration; stem cell biology; tongue papilla; transcriptome; transcriptomics; wound

 DESCRIPTION (provided by applicant): Our long term objectives are to study the development and regeneration of skin ectodermal organs and to apply the principles toward regenerative medicine. Over the last two decades, my laboratory has made a long term commitment to this goal; we have produced several basic scientific discoveries and made conceptual progress toward the advancement of skin regenerative biology. In the next phase, we will consolidate new findings from two recently completed RO1 grants to focus on deciphering the mechanism of phenotypic specification in skin organogenesis, a major challenge in the next phase of cutaneous regenerative medicine. Through progress in stem cell biology and reprogramming technology, scientists are now able to generate epidermal progenitors, in the form of dissociated cells or a keratinocyte monolayer. How to guide these progenitors to form skin with different architecture remains unknown. Understanding these processes is crucial to ensure proper regeneration of a wound graft. A fundamental feature of the skin is the striking regional variation, where distinct skin types (e.g., facial skin and scalp glabrous skin, etc) develop at different body regions to serve different purposes.2,3 We postulate that competent, dissociated, epidermal progenitors interact with dermal cells to form reconstituted skin, a process which is regulated by environmental signals which change over developmental time to generate specific skin appendage phenotypes. We will focus on three fundamental aspects, using the most appropriate animal models for each process. Mouse and human cells are used in Aim 1 whereas chicken skin is used for Aims 2 and 3 because it features remarkable regional differences ideal for experimental analyses. In Aim 1, we will take a multi-disciplinary approach to study how the reconstituted skin layer is generated from dissociated cells. Time-lapse imaging, transcriptome analyses and molecular perturbation will be used to study how the dissociated cells can self-assemble into a layered configuration via a series of multicellular morphological transitions. We will focus on the roles of MMPs in this morphogenetic transition and will attempt to reactivate the morphogenetic ability in adult mouse and human cells by modifying the Wnt-MMP-ECM module. In Aim 2, we will study how skin progenitors are specified during regionalization. Our preliminary data suggests that the conversion of scales to feathers proceeds in a stepwise manner via a hierarchy of signaling molecules. Based on preliminary studies, we will focus on the role of Sox genes in establishing this hierarchy. In Aim 3, we will study the morphogenetic principles of organ shaping. We will focus on the regulation of appendage length using feathers as a model. We will evaluate the hypothesis that complex organ shapes are specified by a "core circuit" that defines a prototypic phenotype qualitatively and "modulator circuits" that modify specific dimensional parameters quantitatively in a temporal-spatial manner. We hypothesize that FGF and Zic signaling, respectively, may be examples of such molecular circuits.

 描述（由申请人提供）：我们的长期目标是研究皮肤外胚层器官的发育和再生，并将其应用于再生医学。在过去的二十年里，我的实验室一直致力于实现这一目标;我们已经取得了一些基本的科学发现，并在皮肤再生生物学的发展方面取得了概念性进展。在下一阶段，我们将巩固最近完成的两项RO 1赠款的新发现，专注于破译皮肤器官发生中表型特异性的机制，这是皮肤再生医学下一阶段的主要挑战。通过干细胞生物学和重编程技术的进步，科学家现在能够以解离细胞或角质形成细胞单层的形式产生表皮祖细胞。如何引导这些祖细胞形成具有不同结构的皮肤仍然是未知的。了解这些过程对于确保伤口移植物的适当再生至关重要。皮肤的基本特征是显著的区域变化，其中不同的皮肤类型（例如，面部皮肤和头皮无毛皮肤等）在不同的身体区域发育，以服务于不同的皮肤。2，3我们假设，有能力的、解离的表皮祖细胞与真皮细胞相互作用以形成重建的皮肤，这是一个受环境信号调节的过程，该环境信号随着发育时间而变化以产生特定的皮肤附属物表型。我们将重点关注三个基本方面，为每个过程使用最合适的动物模型。小鼠和人类细胞用于目标1，而鸡皮用于目标2和3，因为其具有显著的区域差异，非常适合实验分析。在目标1中，我们将采用多学科方法来研究如何从解离细胞中产生重建的皮肤层。延时成像，转录组分析和分子扰动将用于研究解离的细胞如何通过一系列多细胞形态转变自组装成层状结构。我们将专注于MMPs在这种形态发生转变中的作用，并试图通过修改Wnt-MMP-ECM模块来重新激活成年小鼠和人类细胞的形态发生能力。在目标2中，我们将研究如何在区域化过程中指定皮肤祖细胞。我们的初步数据表明，鳞片向羽毛的转化是通过一系列信号分子逐步进行的。基于初步的研究，我们将集中在Sox基因在建立这个层次的作用。在目标3中，我们将研究器官成形的形态发生原理。我们将以羽毛为模型，重点研究附肢长度的调节。我们将评估的假设，复杂的器官形状指定的“核心电路”，定性定义一个原型表型和“调制器电路”，修改特定的尺寸参数定量的时空方式。我们假设FGF和Zic信号分别可能是这种分子回路的例子。