Control of hair follicle cycling

描述（由申请人提供）：毛囊经历受控分解和再生长的连续循环，该过程使人联想到其他生物学过程，如细胞周期和昼夜节律。在最初的形态发生之后，毛囊的下三分之二在称为退化期的阶段中通过免疫细胞的凋亡和浸润而被去除。随后，缩短的卵泡在称为休止期的阶段期间相对静止。随后是毛囊的激活和生长，这一阶段被称为生长期。虽然我们对毛囊形态发生调控的理解已经取得了重大进展，但对可能调控毛发生长周期性特征的生物钟机制知之甚少。我们工作的长期目标是了解毛囊周期的控制。为了解决这个问题，我们采取了基因组学方法，其中我们分析了三个不同毛发生长周期进展期间皮肤中的全局基因表达。然后开发了新的计算算法来识别与毛囊周期相关的基因。我们的发现之一是，时钟调节基因，最有名的是它们在昼夜节律中的作用，显示出惊人的头发周期相关的调节，这表明经典的时钟机制在头发周期中可能发挥作用。与此模型一致，我们发现，中枢时钟基因Clock和Bmal 1突变的小鼠表现出同步生长期的延迟开始。生物钟基因的这种作用似乎是特定于毛囊生长的时间，因为在毛囊中没有观察到形态异常。基于这些发现，我们假设时钟基因在毛发周期控制中起着定时作用。具体来说，我们提出，时钟因子调节毛囊角质形成细胞的细胞周期的控制，通过启动生长期。为了验证这一假设，我们计划首先确定负责生长期启动正常时间的时钟机制的位置。我们将分析具有Bmal1基因的中央缺失和皮肤隔室特异性时钟基因敲除的小鼠的毛发周期。在该提案的第二部分，我们计划开始定义Clock和Bmal 1调节生长期启动正常时间的途径。我们将使用小鼠模型和体外机制研究的组合来发现毛发周期时钟调节的分子机制。这项工作，它的昼夜节律时钟组件链接到一个不同的循环过程，是新颖的，并具有普遍的相关性时钟机制。具体来说，头发生长周期在许多脱发疾病中受到影响，并且在不需要的头发生长中受到影响。这项工作也与再生医学中干细胞和祖细胞的激活有关。此外，毛囊生长机制的失调被认为是许多皮肤癌的基础。 公共卫生相关性：除了与编码头发结构成分的基因突变或由于炎症引起的毛囊结构损伤相关的罕见头发疾病外，大多数脱发疾病和不必要的头发生长都与头发周期异常有关。头发生长的控制中断也与皮肤癌有关。拟议的工作旨在揭示毛囊生长控制的新见解，与干细胞和祖细胞的控制有关，因此与再生医学和一般公共卫生高度相关。

DESCRIPTION (provided by applicant): Hair follicles undergo continuous cycling of controlled breakdown and re-growth in a process that is reminiscent of other oscillary processes such as the cell cycle and circadian rhythm. After the initial morphogenesis, the lower two-thirds of the hair follicle are removed by apoptosis and infiltration of immune cells in a phase referred to as catagen. Subsequently, the shortened follicles are relatively quiescent during a phase referred to as telogen. This is followed by activation and growth of the follicle in a phase referred to as anagen. While significant advances have been made in our understanding of the regulation of hair follicle morphogenesis, less is known about possible clock mechanisms that might regulate the periodic features of hair growth. The long term goal of our work is to understand the control of hair follicle cycling. To address this problem, we have taken a genomics approach wherein we have profiled global gene expression in skin during progression of three distinct hair growth cycles. New computational algorithms were then developed to identify genes that are regulated in relation to hair follicle cycling. One of our findings is that clock regulated genes, best known for their role in circadian rhythm, show a striking hair cycle-related regulation, suggesting possible role for classical clock mechanisms in hair cycling. Consistent with this model, we found that mice mutated for the central clock genes Clock and Bmal1 exhibit delayed onset of synchronized anagen. This effect of clock genes appears to be specific to timing of hair follicle growth because no morphological abnormalities are observed in hair follicles. Based on these findings, we hypothesize that clock genes play a timing role in hair cycle control. Specifically, we propose that clock factors regulate the initiation of anagen through the control of the cell cycle in hair follicle keratinocytes. To test this hypothesis, we plan first to determine the location of clock mechanisms responsible for normal timing of anagen initiation. We will analyze the hair cycle in mice with central deletion of the Bmal1 gene and skin compartment-specific knockouts of clock genes. In the second part of the proposal, we plan to start defining the pathway by which Clock and Bmal1 regulate normal timing of anagen initiation. We will use a combination of mouse models and in vitro mechanistic studies to discover the molecular mechanisms underlying the clock regulation of hair cycling. This work, which links circadian clock components to a different cyclic process, is novel and has general relevance to clock mechanisms. Specifically, the hair growth cycle is affected in many hair loss diseases, and in unwanted hair growth. The work has also relevance to activation of stem and progenitor cells in relation to regenerative medicine. In addition, deregulation of hair follicle growth mechanisms is thought to underlie many skin cancers. PUBLIC HEALTH RELEVANCE: Except for rare hair diseases associated with mutations in genes encoding structural components of the hair or structural damage of hair follicles due to inflammation, most hair loss diseases and unwanted hair growth are linked to hair cycling abnormalities. Disrupted control of hair growth is also associated with skin cancer. The proposed work, which aims to reveal new insights into growth control in hair follicles, has relevance to the control of stem and progenitor cells and is therefore highly relevant to regenerative medicine and public health in general.