Control of hair follicle cycling

描述（由申请人提供）：毛囊在一个与其他振荡过程（如细胞周期和昼夜节律）相似的过程中经历受控分解和再生的连续循环。在最初的形态发生之后，毛囊的下三分之二被细胞凋亡和免疫细胞的浸润所去除，这一阶段被称为退化期。随后，缩短的卵泡在一个称为休止期的阶段相对静止。随后是卵泡的激活和生长，这一阶段被称为生长期。虽然我们对毛囊形态发生的调节的理解取得了重大进展，但对可能调节头发生长周期性特征的时钟机制知之甚少。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，我们采用了基因组学方法，其中我们在三个不同的头发生长周期的进展中描述了皮肤中的全球基因表达。然后开发了新的计算算法来识别与毛囊循环有关的受调节基因。我们的发现之一是，生物钟调节基因（以其在昼夜节律中的作用而闻名）显示出与头发周期相关的惊人调节，这表明经典的生物钟机制可能在头发周期中发挥作用。与该模型一致，我们发现中心时钟基因clock和Bmal1突变的小鼠表现出同步生长的延迟。这种时钟基因的影响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头发周期控制中起计时作用。具体来说，我们提出时钟因子通过控制毛囊角质形成细胞的细胞周期来调节生长期的启动。为了验证这一假设，我们计划首先确定负责正常生长起始时间的时钟机制的位置。我们将分析Bmal1基因中心缺失和皮肤区室特异性敲除时钟基因的小鼠的毛发周期。在提案的第二部分，我们计划开始定义Clock和Bmal1调节正常生长起始时间的途径。我们将使用小鼠模型和体外机制研究相结合的方法来发现头发周期时钟调节的分子机制。这项工作将昼夜节律钟的组成部分与不同的循环过程联系起来，是新颖的，与时钟机制具有普遍的相关性。具体来说，头发的生长周期在许多脱发疾病和多余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，对毛囊生长机制的管制被认为是许多皮肤癌的根本原因。

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.