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

描述（由申请人提供）：皮肤的一个主要功能是产生一个保护屏障，保护我们免受环境的影响。该过程由角质形成细胞干细胞介导，其后代分层和分化，最终形成死细胞和交联蛋白质材料的不溶性支架。这种屏障的形成在胚胎发育期间完成，对生命至关重要。 虽然皮肤在屏障功能中的作用已经得到了很好的证实，但毛囊是否也在这一过程中发挥作用还没有研究。特别是，毛囊漏斗是一个缺乏特征性的领域， 与皮肤上皮相连的细胞。位于毛囊口， 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要和能力。 NIAMS的使命之一是支持深入研究皮肤病的原因，治疗和预防的研究。这一建议是一致的使命，因为我们的长期目标是在胚胎发育，成人稳态和疾病扰动漏斗细胞的特点。事实上，包括寻常痤疮在内的各种皮肤病都特别发生在漏斗部，在更严重的情况下，可能会导致该区域破裂（并可能破坏屏障功能），导致炎症性疾病。这项建议旨在阐明漏斗，着眼于阐明痤疮的机械原因。 在具体目标1中，我们将分离新生和成年小鼠漏斗细胞，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在形成漏斗部分化的基底上层时的运动。这个开放目标的结果将提高我们对该领域的理解，并提供用于后续目标的工具和标记。 在特定目标2中，我们将通过破坏在小鼠中产生漏斗的干细胞中特异性的Notch通路组分来测试Notch信号传导在漏斗中的作用。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发挥作用，并可能导致产生改进的痤疮小鼠模型。 在具体目标3中，我们将研究Notch信号传导和分化缺陷是否是人类痤疮形成的基础。这将通过分析一组标记物来完成，包括在痤疮治疗之前和之后的患者中的Notch信号传导和漏斗。这些转化研究将补充我们在小鼠中的基础实验，并有望为这种疾病的原因提供机制性见解

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