Elucidation of the hr-dependent pathway of hair growth

描述(摘自申请者的摘要)：最近，进展 了解毛囊(HF)的形态发生 生物学；然而，毛发生长控制的分子和遗传方面 在很大程度上仍然不为人知。其中，HF退行性变的分子途径 转型是人们最不了解的，尽管 退行性疾病是人类许多常见的毛发疾病的基础。近期 研究表明，降钙素是一个由细胞凋亡和程序化细胞驱动的过程 死亡是卡他素HF转化的主要机制。以前的研究 提示HF基质的异位和过早凋亡是其主要缺陷。 在突变的hr/hr无毛小鼠皮肤中，导致完全脱发。 这些发现暗示无毛(Hr)基因是协调的关键因素。 HF退行性变和程序性细胞死亡过程中的基本细胞过程 可能是hr基因活性的关键靶点。为了进一步深入了解 在分子控制HF的功能上，他们提出了利用天然的 来自突变(hrrh/hrrh)无毛的皮肤和培养的角质形成细胞 以小鼠为模型阐明HR基因在细胞周期调控中的作用 细胞凋亡驱动的增生素及其下游靶点的识别 人力资源基因的活性。HR基因参与细胞凋亡的假说 将使用形态学方法、TUNEL和 Annexin V染色与功能实验(比较 UVB照射下小时/小时和WT开始时细胞凋亡相关基因的表达 照射，用DFMO、ICE和caspase-3抑制剂治疗)。vbl.使用 Northern印迹分析和免疫组织化学，他们将检测表达 依赖人力资源的监管的假定下游目标的模式 WT和小时/小时皮肤中的路径。HR基因未知靶点的寻找 活动将使用与核酸杂交的阵列进行 从完整的hrrh/hrrh和wt基因的小鼠表皮中分离得到。 已识别的候选目标基因将根据其已知的 在毛囊生理学中的作用，也根据从 功能实验和免疫组织化学研究。因此，这些实验 在这份提案中概述的是旨在剖析细胞和分子 利用无毛表型研究毛囊退行性变的机制 作为一个实验模型。

DESCRIPTION (Taken from the applicant's abstract): Recently, progress has been achieved in the understanding of the morphogenic aspects of hair follicle (HF) biology; nevertheless, the molecular and genetic aspects of hair growth control remain largely unknown. Among these, the molecular pathways of HF catagen transformation are the least well understood despite the abnormalities of catagen progression underlie many common hair disorders in humans. Recent studies showed that catagen is an apoptosis-driven process and programmed-cell death is the major mechanism of catagen HF transformation. Previous studies indicated that ectopic and premature apoptosis in HF matrix is the major defect in the mutant hr/hr hairless mouse skin that causes the complete hair loss. These findings implicate the hairless (hr) gene as a key factor in coordinating basic cellular processes during HF catagen and programmed cell death as a possible key target of hr gene activity. In order to gain further insights into the molecular control of HF functions by hr, they propose the use of the native skin and cultured keratinocytes derived from the mutant (hrrh/hrrh) hairless mice as a model for elucidation the role of hr gene in regulation of apoptosis-driven catagen and for the identification of the downstream targets of hr gene activity. The hypothesized involvement of hr gene into apoptotic regulatory pathway will be tested using morphological methods, TUNEL and annexin V staining along with functional experiments (comparison of apoptosis-associated gene expression in hr/hr and wt start under UVB irradiation, treatment with DFMO and ICE and caspase-3 inhibitors). Using Northern blot analysis and immunohistochemistry, they will test the expression patterns of presumptive downstream targets of the hr-dependent regulatory pathway in wt and hr/hr skin. The search for unknown targets of hr gene activity will be performed using hybridization arrays with nucleic acids isolated from intact mouse epidermis of both hrrh/hrrh and wt genotypes. Identified candidate target genes will be prioritized according to their known role in hair follicle physiology, and also according to data obtained from functional experiments and immunohistochemical studies. Thus, the experiments outlined in this proposal are designed to dissect the cellular and molecular mechanisms of hair follicle catagen transformation using the hairless phenotype as an experimental model.