The Hair Follicle Infundibulum: A Potential Mediator of Skin Barrier Function

毛囊漏斗部：皮肤屏障功能的潜在调节者

• 批准号: 9244732
• 负责人: Sunny Y Wong
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244732
• 关键词: Acne; Acne Vulgaris; Adult; Animal Model; Animals; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Characteristics; Complement; Cyst; Data; Defect; Dehydration; Dermis; Development; Disease; Embryo; Embryonic Development; Environment; Epidermis; Epithelial; Epithelium; Eye; Gene Expression Profile; Gene Expression Profiling; Generations; Hair; Hair follicle structure; Homeostasis; Human; Inflammatory; Lead; Life; Light; Mediating; Mediator of activation protein; Mission; Morphogenesis; Movement; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Notch Signaling Pathway; Oral cavity; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Population; Prevention; Process; Property; Reaction; Regulation; Research Support; Role; Rupture; Sampling; Sebaceous Glands; Sebum; Series; Signal Transduction; Site; Skin; Specific qualifier value; Specimen; Stem cells; Stratification; Structure; System; Testing; Time; Work; biomarker panel; cell motility; crosslink; experimental study; improved; insight; keratinocyte; mouse model; neglect; notch protein; prevent; public health relevance; scaffold; skin barrier; skin disorder; targeted treatment; tool; transcriptome sequencing; translational study

DESCRIPTION (provided by applicant): A major function of the skin is to generate a protective barrier that shields us from our environment. This process is mediated by keratinocyte stem cells whose progeny stratify and differentiate, eventually forming an insoluble scaffold of dead cells and cross-linked proteinaceous material. Formation of this barrier is completed during embryonic development and is essential for life. Although the skin's role in barrier function is well-established, whether the hair follicle also plays a role in this process hs not been studied. In particular, the hair follicle infundibulum is a poorly characterized domain of cells that appears continuous with the skin epithelium. Situated at the mouth of the hair follicle, infundibular cells are multi-layered and exposed to the outer environment. These characteristics suggest both the need and capacity for infundibular cells to form a barrier. One of the missions of NIAMS is to support research that delves into the causes, treatment, and prevention of skin diseases. This proposal is concordant with that mission since our long-term objective is to characterize infundibular cells during embryonic development, adult homeostasis and disease perturbation. Indeed, a variety of skin disorders, including acne vulgaris, arises specifically at the infundibulum, and in more severe cases may cause rupture of this domain (and, presumably, disrupt barrier function), leading to inflammatory disease. This proposal seeks to shed light on the infundibulum, with an eye towards elucidating the mechanistic causes of acne. In Specific Aim 1, we will isolate both nascent and adult mouse infundibular cells, and characterize their gene expression patterns by RNA-Sequencing. We will also analyze in detail the movement of these cells as they form the differentiated, suprabasal layers of the infundibulum. Results from this opening Aim will improve our understanding of this domain, and provide tools and markers for use in the subsequent Aims. In Specific Aim 2, we will test the role of Notch signaling in the infundibulum by disrupting Notch pathway components specifically in the stem cells that give rise to the infundibulum in mice. Importantly, this will enable us to assess whether the hair follicle itself plays a role in barrier function, and may lead to the generation of improved mouse models of acne. In Specific Aim 3, we will examine whether Notch signaling and differentiation defects underlie acne formation in humans. This will be accomplished by analyzing a panel of markers, both for Notch signaling and the infundibulum, in patients prior to and after acne therapy. These translational studies will complement our basic experiments in mice, and will hopefully provide mechanistic insights into the causes of this disease

描述（由申请人提供）：皮肤的主要功能是产生保护我们免受环境的保护屏障。该过程由角质形成细胞细胞介导，后代分层和分化，最终形成了死细胞的不溶性支架和交联的蛋白质材料。这种障碍的形成是在胚胎开发过程中完成的，对生命至关重要。 尽管皮肤在屏障功能中的作用是良好的，但是毛囊是否在此过程中也没有研究HS。特别是，毛囊的ifundibulum是一个特征较差的域 与皮肤上皮连续的细胞。位于毛囊的口中， 漏斗细胞是多层的，并暴露于外部环境。这些特征表明，漏斗细胞形成屏障的需求和能力。 NIAMS的任务之一是支持研究皮肤疾病的原因，治疗和预防的研究。该提议与该任务一致，因为我们的长期目标是在胚胎发育，成人稳态和疾病扰动过程中表征漏斗细胞。实际上，包括痤疮的各种皮肤疾病是在iNfundibulum出现的，在更严重的情况下可能会导致该结构域破裂（大概是中断的屏障功能），导致炎症性疾病。该提议试图阐明漏斗，并着眼于阐明痤疮的机械原因。 在特定的目标1中，我们将隔离新生和成年小鼠的漏斗细胞，并通过RNA测序表征其基因表达模式。我们还将详细分析这些细胞形成漏斗的分化的上额层时的运动。这个开场目标的结果将改善我们对该领域的理解，并提供在后续目标中使用的工具和标记。 在特定的目标2中，我们将通过破坏在干细胞中的Notch途径成分来测试Notch信号在Infundibulum中的作用，从而导致小鼠的漏斗。重要的是，这将使我们能够评估毛囊本身是否在屏障功能中起作用，并可能导致改善痤疮小鼠模型的产生。 在特定的目标3中，我们将检查人类痤疮形成的凹口信号传导和分化缺陷。这将通过分析痤疮治疗前后的患者分析一组标记物，包括Notch信号传导和Infundibulum。这些翻译研究将补充我们在小鼠中的基本实验，并有望为这种疾病的原因提供机械见解