Rab23促进UVB照射诱导黑素小体转运的作用及其分子机制研究

Hyperpigmentation caused by UVB radiation is very common, which mechanism include multiple steps involved in the pathogenesis of melanin metabolism. Melanin is biosynthesized in the melanosome at the perinuclear region of the melanocyte. And then the melanin accumulated in the mature melanosome is transported to the periphery through the dendritic cells. Inresponse to UVB light, the melanin pigments contained in melanocytes are transferred to the surrounding keratinocytes through the tips of the dendrites to protect against UV light damage or carcinogenesis. Therefore, melanosome transportation is one of the most important steps involved hyperpigmentation caused by UVB radiation. . Although the regulation of melanosome transportation is complicated, it has been reported that Rac1 and MITF are the key regulators for dendrite formation and melanosome transportation. So far, however, our comprehension of the mechanism of melanosome transportation remains only fragmentary. . Supported by NSFC grant, we found high expression of Rab23 in melanocytes after UVB radiation firstly, and then, we noted that over-expression Rab23 can significantly increased dendrite formation and melanosome transportation, and moreover, knockdown of Rab23 by siRNA significantly reduced dendrite formation and melanosome transportation. We also observed in further studies that the expression of Rac1 and MITF could change with Rab23 level, suggesting that Rac1 and MITF, the key regulators for dendrite formation and melanosome transportation, could be somehow regulated by Rab23.. However, the molecular mechanism by which Rab23 enhance dendrite formation and melanosome transportation still remains unclear. Therefore, the aim of this study is to comprehensively clarify the mechanism underlying Rab23 promoting melanosome transportation. With stable cell lines of different Rab23 activity, we are to analyze the correlation of expression of Rab23 and Rac1 and MITF in melanocytes after UVB radiation, to explore whether Rac1 and MITF play a central role in the regulation of melanosome transportation enhanced by Rab23, to identify the molecular mechanism of Rab23-regulating MITF and Rac1, to find downstream effectors of Rac1 and MITF, which play an important role in mediating dendrite formation and melanosome transportation promoted by Rab23.. The anticipated results will clarify the molecular mechanism underlying Rab23 enhanced the dendrite formation and melanosome transportation through regulating Rac1 and MITF, help understanding the new functions of Rab23, and possiblly provide a new strategy and new target for the treatment of hyperpigmentation caused by UVB radiation.

UVB照射所致色素沉着十分常见，发病机制涉及黑素代谢的多个步骤，其中黑素小体转运增强是重要的环节。研究表明，Rac1和MITF是调控黑素小体转运的关键分子。我们前期发现，黑素细胞中Rab23在UVB照射后表达增高，并显著促进黑素小体的转运，进一步研究显示Rab23可调控Rac1和MITF的表达，表明Rab23积极参与了黑素小体转运的调控，但具体机制不清。本研究拟在此基础上，深入研究Rab23调控黑素小体转运的分子机制：明确Rac1和MITF在Rab23促进黑素小体转运中的关键作用，探讨Rab23调控Rac1和MITF的分子机制，确定Rab23调控Rac1和MITF促进黑素小体转运的效应分子，为全面阐明Rab23促进黑素小体转运的分子机制奠定基础。预期结果将有助于深入认识Rab23的功能及作用，完善Rab23调控黑素小体转运机制，并为UVB诱导色素沉着的防治提供新的策略和治疗靶点。

UVB照射所致色素沉着十分常见，发病机制涉及黑素代谢的多个步骤，其中黑素小体转运增强是重要的环节。我们前期研究提示Rab23积极参与了黑素小体转运的调控，但具体机制不清。本课题目的旨在明确Rab23在UVB照射诱导的黑素小体成熟及转运中的作用，观察Rac1和MITF对Rab23促进黑素小体转运的影响及机制，为全面阐明Rab23促进黑素小体转运的分子机制奠定基础。本研究首先在组织学方面观察了Rab23在色素痣及恶性黑素瘤组织中的表达情况，并分析其与黑素细胞来源肿瘤恶性程度的相关性及临床意义，发现Rab23在恶性黑素瘤组织中的表达程度明显增高；随后观察了UVB照射对黑素细胞增殖、黑素细胞树突形成及黑素小体转运的影响及机制，发现UVB照射可诱导培养黑素细胞其树突延长，明显促进黑素细胞树突形成，促进黑素小体向角质形成细胞的转运和转移；并证实了Rab23积极参与了UVB照射诱导的早期黑素小体成熟并向树突末端的转运过程，进一步机制研究发现Rab23可通过与MITF相互作用影响UVB诱导的黑素细胞黑素合成，并通过与Rac1相互作用影响UVB诱导的黑素小体转运，深入的具体机制可能与调控细胞自噬相关分子有关。上述结果有助于深入认识Rab23调控黑素小体的转运机制，并为UVB诱导色素沉着的防治提供新的策略和治疗靶点。