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：掌跖（足底和手掌）皮肤增厚的表皮表达了 结构蛋白的独特组合有助于其卓越的抗性 生物力学应力。与邻近皮肤相比，PP 皮肤的色素沉着也较低， 无毛且具有高密度的小汗腺 (EG)。先前的研究 表明表皮的区域特异性分化是强加于 胚胎/围产期发育期间的角质形成细胞，但一旦明确， 角质形成细胞对其起源部位产生内在的表观遗传记忆。嫁接和 培养实验表明这种记忆是不完整的，并且来自 原位真皮维持并增强适当的 PP 分化，同时发出信号 来自异位真皮的细胞可以促进选择性分化。这些研究已 由于依赖一组有限的标记而受到阻碍。这里建议的工作采用 转基因小鼠创建了全面的分子描述 通过 RNAseq 进行特异性表皮分化并识别来自 真皮在发育过程中促进分化。诱发的增益和损失 产生双背足和双腹足的基因的功能被用来探索产生双背足和双腹足的基因的功能 指定鞋底区域角质形成细胞身份的感应信号是 维持成人特定位点表皮分化所需的。我们还问 操纵完整皮肤中的这些信号是否会刺激其他皮肤的表皮 身体各部位采用鞋底表皮特征的各个方面。顺利完成 这项工作将解决有关内在角质形成细胞相对重量的争议 特征与来自完整成人皮肤真皮的持续感应信号。这是 旨在提供见解，可能会导致新的方法来赋予卓越 被迫承担承重职责的患者皮肤的表现， 例如，当腿部截肢将这种功能强加于更近端的肢体皮肤时。