Molecular Regulation of Hair Follicle Morphogenesis

毛囊形态发生的分子调控

• 批准号: 7913746
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 34.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-07 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913746
• 关键词: Address; Adult; Basal cell carcinoma; Binding; Biology; Birth; Cell physiology; Cells; Clinical Treatment; Clinical Trials; Complex; Data; Development; Disease; Drug usage; Ectopic Expression; Embryo; Embryonic Development; Epithelial; Epithelial Cells; Epithelium; Erinaceidae; Gene Expression; Gene Targeting; Germ; Goals; Graafian Follicles; Grant; Growth; Growth and Development function; Hair; Hair follicle structure; In Vitro; Knowledge; LacZ Genes; Lead; Life; Ligands; Link; Maintenance; Malignant Neoplasms; Molecular; Morphogenesis; Mus; Natural regeneration; Organ; Pathogenesis; Pathway interactions; Patients; Phase; Physiological; Regulation; Reporter; Rest; Resting Phase; Role; Sebaceous Glands; Signal Pathway; Signal Transduction; Skin; Staging; Stem cells; Stimulus; Structure; Study models; Testing; Time; Tissues; Toxic effect; Transcription Repressor/Corepressor; Transducers; Work; base; cancer type; cell growth; hair follicle disorder; improved; in vivo; inhibitor/antagonist; insight; keratinocyte; novel strategies; postnatal; public health relevance; receptor; research study; self-renewal; skin disorder; tissue regeneration; transcription factor

DESCRIPTION (provided by applicant): The long-term goal of this grant is to further our understanding of the molecular regulation of hair follicle development and cycling, with the hope that this new knowledge will provide clues to the pathogenesis of hair follicle disorders and lead to new approaches to therapy. The follicle is a powerful model for studying pathways controlling organ development and regeneration. Throughout much of adult life, follicles cycle through an active growth phase, called anagen; a regression phase, catagen; and a resting phase, telogen. Numerous factors and pathways are required for proper hair follicle development and cycling: our work has centered largely on the Hedgehog (Hh)/Gli pathway. Normally, the Hh/Gli pathway is repressed since the Hh receptor Ptch1 inhibits Smo, a key signal transducer in this pathway. Secreted Hh binds to Ptch1 and inhibits it function, relieving the inhibition of Smo, which is then free to activate signaling and ultimately modulate gene expression via Gli transcription factors. The Hh/Gli pathway has well-established functions during embryonic and postnatal hair follicle growth, where it provides a major proliferative stimulus to epithelial cells as they rapidly expand to build the mature, anagen hair follicle. However, essentially nothing is known of the role of Hh/Gli activity in a small subset of cells in the resting, telogen follicle, which was just recently discovered. In addition, the function of sustained Hh/Gli signaling in mature, anagen hair follicles is also not known. We propose to address both of these questions using several complementary in vivo approaches, which will enable us to block Hh/Gli signaling at different levels in the pathway, and at specific times during the hair cycle. We also propose to test the role of the transcriptional repressor Bmi1, a Hh/Gli target in other organs, in hair follicle biology. The results of these studies will fill in major gaps in our understanding of how Hh/Gli signaling contributes to the complex regulation of hair follicle biology, and may yield clues into the pathogenesis of hair follicle disorders. More globally, they will provide fundamental insight into pathways that are utilized by many other organs for growth and regeneration, and are commonly deregulated in cancer. Finally, since several Hh pathway inhibitors are currently in clinical trials, these studies are timely as they will lead to a better understanding of potential toxicities associated with the use of these drugs in patients. PUBLIC HEALTH RELEVANCE: Abnormalities in the hair follicle and related structures are responsible for many common skin diseases and hair loss disorders. The experiments in this grant will increase our understanding of the control mechanisms that regulate hair follicle growth and development. This knowledge should lead to new and improved treatments for hair follicle-related skin diseases.

描述（由申请人提供）：这笔赠款的长期目标是进一步了解毛囊发育和骑自行车的分子调节，希望这种新知识能为毛囊疾病的发病机理提供线索，并带来新的治疗方法。卵泡是研究控制器官发育和再生的途径的强大模型。在整个成人生活的大部分时间里，卵泡循环穿越活跃的生长阶段，称为Anagen。回归阶段，catagen;和一个静止阶段，telogen。适当的毛囊发育和循环需要许多因素和途径：我们的工作主要集中在刺猬（HH）/GLI途径上。通常，由于HH受体PTCH1抑制SMO，SMO是该途径中的键信号传感器，因此HH/GLI途径被抑制。分泌的HH与PTCH1结合并抑制其功能，从而缓解了SMO的抑制作用，然后自由激活信号传导并最终通过GLI转录因子调节基因表达。 HH/GLI途径在胚胎和产后毛囊生长过程中具有良好的功能，它为上皮细胞提供了主要的增殖刺激，因为它们迅速扩展以构建成熟的Anagen毛囊。然而，从本质上讲，HH/Gli活性在静息肠卵泡中的一小部分细胞中的作用尚未知道，这是最近才发现的。另外，尚不清楚成熟的HH/GLI信号传导的持续HH/GLI信号传导的功能。我们建议使用几种互补的体内方法解决这两个问题，这将使我们能够在途径中以及在头发周期中的特定时间内阻止HH/GLI信号传导。我们还建议测试其他器官中HH/GLI靶标在毛囊生物学中的转录阻遏物BMI1的作用。这些研究的结果将填补我们对HH/GLI信号如何促进毛囊生物学的复杂调节的主要空白，并可能导致毛囊疾病发病机理的线索。在全球范围内，它们将提供对许多其他器官用于生长和再生使用的途径的基本见解，并且通常在癌症中放松管制。最后，由于目前正在进行临床试验中，由于有几种HH途径抑制剂，因此这些研究将及时，因为它们将更好地了解与患者使用这些药物有关的潜在毒性。 公共卫生相关性：毛囊和相关结构的异常是导致许多常见的皮肤疾病和脱发疾病。该赠款中的实验将增加我们对调节毛囊生长和发育的控制机制的理解。这些知识应导致与毛囊相关皮肤疾病的新治疗方法。