Inductive properties of the dermal papilla of the hair follicle

描述(申请人提供)：毛囊已经成为一个重要的研究重点，不仅是因为脱发或毛发过度生长对心理和情感的影响，还因为毛囊是由成人常驻干细胞群体定期再生的，这是干细胞生物学、再生医学和器官发生学中的一个重要模型系统。毛囊由两个主要组成部分组成，(1)上皮群，它构成毛囊的大部分，并产生分化的细胞，形成毛干及其周围的毛囊细胞层；(2)专门的间充质群，即真皮乳头，指导这些上皮细胞的活动。我们已经开发出在毛囊形成后控制毛乳头基因表达的方法，并利用这些方法来研究毛乳头和毛囊上皮之间的信号转导。这提供了对冲击DP细胞的信号的洞察，以控制信号的产生，进而调节角质形成细胞的行为和毛发生长。这些实验提出了第二种控制毛发大小和形状的机制，这种机制通过主动和动态地调节每个毛囊中DP细胞的数量而发生。毛发的大小与DP细胞/毛囊的数量相关。这项研究的目的之一是通过选择性地消融成人毛囊中的DP细胞来测试这种相关性的意义，并评估对毛发生长和周期的影响以及可能补偿DP室细胞死亡的机制。第二个是鉴定在DP中表达的转录因子Sox2的作用。我们在删除Sox2基因后观察到的表型表明，在卵泡再生的关键时期，Sox2基因对DP大小起调节作用。我们将通过获得功能和挽救实验来验证这一假说，并确定在DP中介导Sox2功能的基因表达变化。毛囊内部和毛囊之间的信号，以及皮肤周围细胞类型的信号都有助于指定DP大小。为了表征这些信号，我们将使用DP特异性阻断额外的信号通路来扩展我们的研究，以表征它们如何对这两个机制做出贡献，即每个DP细胞的信号产生和DP细胞数量的调节。这项工作的成功完成将使人们深入了解祖细胞池与其生态位相互作用和塑造其生态位的机制，以及在生物体不断变化的需求的背景下，该利基如何有助于调节器官的大小和形状。

DESCRIPTION (provided by applicant): The hair follicle has emerged as an important focus of research not only because of the psychological and emotional impacts of hair loss or excessive hair growth, but also because the hair follicle is periodically regenerated from a resident stem cell population in the adult and this serves an important model system in stem cell biology, regenerative medicine, and organogenesis. The hair follicle is composed of two principle components, (1)an epithelial population that comprises the majority of the follicle and gives rise to the differentiated cells that form the hair shaft and its surrounding cell layers in the follicl, and (2) a specialized mesenchymal population, the dermal papilla, that guides the activities of these epithelial cells. We have developed methods to manipulate gene expression specifically in the dermal papilla of the hair follicles after they have formed and exploited these to study the signaling between the dermal papilla and the follicular epithelium. This has provided insight onto signals that impinge on DP cells to control the production of signals that in turn regulate keratinocyte behavior and hair growth. These experiments suggest a second mechanism dictating the size and shape of the hair produced that occurs through active and dynamic regulation of the number of DP cells per follicle. The size of the hair correlates with the number of DP cells /follicle. One aim of this research is to test the significance of this correlation by selectively ablating DP cells in adult hair follicles and evaluating both the effects on hair growt and cycling as well as mechanisms that may compensate for cell death in the DP compartment. A second is to characterize the role of a transcription factor, Sox2 that is expressed in the DP. The phenotypes we observe after deleting the Sox2 gene specifically in the DP suggests it acts to regulate DP size during a critical period in follicular regeneration. We will test this hypothess with gain of function and rescue experiments and identify the gene expression changes that mediate Sox2 function in the DP. Signals within and between follicles, as well as from surrounding cell types in the skin all contribute to specifying DP size. To characterize those signals, we will extend our studies using DP specific blockade of additional signaling pathways to characterize how they contribute to these two mechanisms, signal production per DP cell and regulation of DP cell number. Successful completion of this work will provide insight into the mechanisms by which a progenitor pool interacts with and molds its niche and how that niche contributes to the regulation organ size and shape in the context of the changing needs of the organism.