Control of hair follicle cycling

描述(申请人提供)：毛囊经历受控的破裂和再生长的连续循环过程，这一过程使人想起其他摆动过程，如细胞周期和昼夜节律。在最初的形态形成后，通过细胞凋亡和免疫细胞的渗透，毛囊的下部三分之二被移除，这一阶段被称为退化期。随后，缩短的卵泡在被称为端原的阶段相对静止。紧随其后的是卵泡的激活和生长，这一阶段称为生长期。虽然我们对毛囊形态发生的调控已经取得了重大进展，但对可能调节毛发生长周期特征的可能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，我们采取了基因组学的方法，其中我们描绘了皮肤在三个不同的毛发生长周期中的全球基因表达。然后开发了新的计算算法来识别与毛囊周期有关的调控基因。我们的发现之一是时钟调节基因，以其在昼夜节律中的作用而闻名，显示出与毛发周期相关的显著调节，这表明经典的时钟机制在毛发周期中可能发挥作用。与这一模型一致，我们发现中枢时钟基因Clock和BMal1突变的小鼠表现出同步生长期的延迟开始。时钟基因的这种作用似乎与毛囊生长的时间有关，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计时作用。具体地说，我们认为时钟因素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生长期启动正常时间的时钟机制的位置。我们将分析中心缺失BMal1基因和皮肤室特异性Clock基因敲除的小鼠的毛发周期。在提案的第二部分，我们计划开始定义CLOCK和BMAL1调节生长期启动的正常时间的途径。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毛发周期时钟调节的分子机制。这项将昼夜节律时钟分量与不同的周期过程联系起来的工作是新颖的，与时钟机制具有普遍的相关性。具体地说，毛发生长周期在许多脱发疾病和不想要的毛发生长中受到影响。这项工作也与与再生医学有关的干细胞和祖细胞的激活有关。此外，毛囊生长机制的松弛被认为是许多皮肤癌的基础。 与公共卫生相关：除了罕见的毛发疾病与毛发结构成分编码基因突变或炎症导致的毛囊结构破坏有关外，大多数脱发疾病和不希望看到的毛发生长都与毛发周期异常有关。对毛发生长控制的中断也与皮肤癌有关。这项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相关，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.