遗传性单纯性少毛症新致病基因RPL21功能及致病机制研究

Hereditary hypotrichosis simplex (HHS) is a rare autosomal dominant form of congenital hair loss disorders characterized by generalized hair loss without characteristic hair shaft changes and anomalies in other organ systems. Our previous studies have revealed a new gene, RPL21, as the causative gene of HHS for the first time. The RPL21 gene encodes a ribosomal protein that is a component of the 60S subunit, ribosomal protein L21. However, there is lack of functional study of RPL21 and little is known regarding the mechanism how RPL21 mutation leads to hair loss. In this study, the expression of RPL21 in the hair follicle and the scalp skin of the patients and normal controls will be studied. The expression and subcellular localization of RPL21 in cultured HEK 293T cells will be explored. Knocking down of RPL21 by siRNA in HEK 293T cells and its effect on HEK 293T cells will be found out. DNA microarrays for gene expression profiles will be used to find the differential expression genes before and after Knocking down of RPL21, and to reveal the pathways which RPL21 might be involved in. Perturbations to ribosome biogenesis have been demonstrated to induce an acute stress response leading to p53 activation through the inhibition of MDM2 by a number of ribosomal proteins. To clear whether RPL21 could lead to p53 activation via the ribosomal protein-MDM2-p53 pathway, human p53-proficient osteosarcoma U2OS cells were cultured and interaction between RPL21 and MDM2 will be studied by co-immunoprecipitated. The effect on the cell cycle, cell proliferation and apoptosis caused by knocked-down RPL21 will be tested. The relationship between knocking-down RPL21 and p53 activation as well as the mechanism of p53 activation is to be studied. This study is of great importance to the pathogenesis study of HHS, and set a basis for us to reveal the role of RPL21 in the mechanism for control of hair growth and ribosome biogenesis.

遗传性单纯性少毛症（HHS）是一种常染色体显性遗传的先天性秃发性疾病，累及全身毛发，而其它器官系统正常。本课题组首次发现RPL21为该病的新致病基因。RPL21是核糖体60S大亚基的重要组成蛋白之一，目前尚无其功能研究报道，其突变致病机制不清。本课题拟在前期研究基础上对RPL21在人头皮、毛囊和培养HEK 293T细胞进行RPL21表达的研究；通过RNAi敲低HEK 293T细胞RPL21，研究其对细胞的影响，通过表达谱芯片寻找可能受RPL21调节的相关蛋白及信号通路；为探讨RPL21是否通过核糖体蛋白-MDM2-p53通路而激活p53基因，拟利用培养U2OS细胞研究RPL21与MDM2的相互作用，敲低RPL21与p53激活的关系和影响机制，及其对细胞生长周期、增殖及凋亡的影响。本研究对于揭示HHS的发病机制有重要意义，将为深入研究RPL21在毛囊生长调控和核糖体生物合成中的作用奠定基础。

遗传性单纯性少毛症（HHS）是一种常染色体显性遗传的先天性秃发性疾病，累及全身毛发，而其它器官系统正常。本课题组首次发现RPL21 为该病的新致病基因，RPL21是核糖体60S 大亚基的重要组成蛋白之一，目前尚无其功能研究报道，其突变致病机制不清。本课题通过对RPL21基因的功能和致病机制的初步探索，首次明确了RPL21在正常成人及胎儿头皮组织中主要表达在基底层以上的表皮，以及毛囊的内、外毛根鞘、隆突部以及皮下脂肪，而不是表皮基底层、毛囊基质以及毛囊乳头。我们发现RPL21参与人永生化细胞系HaCaT细胞的增殖、细胞周期、凋亡过程，尤其是在HaCaT细胞的分化中可能具有重要作用。本研究为RPL21在人毛囊及表皮中作用的研究以及揭示HHS 的发病机制奠定了基础，也为毛囊生长调控和分化的研究提供了新的方向。

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