Development and maintenance of plantar skin

足底皮肤的发育和保养

• 批准号: 10399418
• 负责人: BRUCE A MORGAN
• 金额: $ 17.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399418
• 关键词: Adopted; Adoption; Adult; Amputation; Amputation Stumps; Appearance; Biomechanics; Body Regions; Characteristics; Data; Data Set; Dermal; Dermis; Development; Disease; Distal; Dorsal; Eccrine Glands; Embryo; Epidermis; Exhibits; Foundations; Future; Gene Expression; Gene Structure; Genes; Genetic; Goals; Hair follicle structure; Hand; Health; Hindlimb; In Vitro; Knowledge; Lead; Leg; Life; Limb Bud; Limb structure; Maintenance; Memory; Molecular; Mus; Newborn Infant; Patients; Performance; Pigments; Property; Research; Resistance; Role; Signal Induction; Signal Transduction; Site; Skin; Specific qualifier value; Stress; Structural Protein; Structure; Testing; Thick; Tissue-Specific Gene Expression; Trauma; Weight; Weight-Bearing state; Wild Type Mouse; Work; density; design; epigenetic memory; experimental study; foot; gain of function; gene function; genetic manipulation; improved; in vivo; insight; keratinocyte; limb amputation; loss of function; man; novel strategies; perinatal development; postnatal development; regional difference; tool; transcriptome sequencing; transdifferentiation

Abstract: The thickened epidermis of palmoplantar (sole and palm) skin expresses a unique combination of structural proteins that contribute to its superior resistance to biomechanical stress. PP skin is also hypo-pigmented when compared with adjacent skin, is hairless and exhibits a high density of eccrine sweat glands (EG). Prior research demonstrates that regional specific differentiation of the epidermis is imposed on keratinocytes during embryonic/perinatal development but that once specified, keratinocytes develop an intrinsic epigenetic memory of their site of origin. Grafting and culture experiments suggest that this memory is incomplete, and that signaling from orthotopic dermis sustains and augments appropriate PP differentiation, while signals from heterotopic dermis can promote alternative differentiation. These studies have been hampered by reliance on a limited set of markers. The work proposed here employs genetically modified mice to create a comprehensive molecular description of sole- specific epidermal differentiation by RNAseq and identify inductive signals from the dermis that promote that differentiation during development. Inducible gain and loss of function of genes that generate bi-dorsal and bi-ventral feet are used to explore the extent to which the inductive signals that specify regional keratinocyte identity in the sole are required to maintain site-specific epidermal differentiation in the adult. We also ask whether manipulation of those signals in intact skin can provoke epidermis in other regions of the body to adopt aspects of sole epidermal character. Successful completion of this work will settle controversies about the relative weight of intrinsic keratinocyte characteristics vs. ongoing inductive signaling from dermis in intact adult skin. It is designed to provide insights that may lead to novel approaches to conferring superior performance on patient skin that has been forced to assume load-bearing duties, for example when leg amputation imposes this function on more proximal limb skin.

摘要：Palmoplantar（鞋底和棕榈）皮肤增厚的表皮表达 结构蛋白的独特组合，有助于其优越的抗性 生物力学应力。与邻近皮肤相比，PP皮肤也会不足。 无毛，表现出高密度的Eccerine汗腺（例如）。先前的研究 证明表皮的区域特异性分化被施加 胚胎/围产期发育过程中的角质形成细胞，但一旦指定， 角质形成细胞形成其原产地点的内在表观遗传记忆。嫁接和 培养实验表明此记忆不完整，并且发出信号 原位真皮可维持和增强适当的PP差异化，而信号 来自异位真皮可以促进替代分化。这些研究已经 由于依赖有限的标记而受到阻碍。这里建议的工作雇用 基因修饰的小鼠，以创建鞋底的综合分子描述 通过RNASEQ进行特定的表皮分化，并确定来自 促进发展过程中这种分化的真皮。诱导的增益和损失 产生双向和双层脚的基因的功能用于探索程度 唯一指定区域角质形成身份的归纳信号是 需要维持成人特定地点表皮分化。我们也问 在完整皮肤中操纵这些信号是否会引起其他表皮 人体采用唯一表皮特征的各个方面。成功完成 这项工作将解决有关内在角质形成细胞相对重量的争议 特征与完整成人皮肤真皮的持续感应信号传导。这是 旨在提供可能导致新方法授予上级的见解 在患者皮肤上的表现被迫承担负载职责，因为 示例腿截肢将此功能强加于近端的肢体皮肤。