BMP受体棕榈酰化在神经干细胞中的作用及机制研究

Neural stem cells play essential roles in the development and repair of the nervous system. However, how self-renewal and differentiation of NSCs is controlled remains unclear. Recent studies show that protein post-translational palmitoylation regulates protein stability, localization and/or protein-protein interaction, and thus affecting cell proliferation and differentiation. Our preliminary studies show that inhibition of palmitoyl acyltransferases with 2-bromopalmitate (2-BP) altered the differentiation process of NSCs, which is associated with change in the activation of BMP-Smad1 and BMP-MAPKs pathways. Treatment of NSCs with BMP2 could restore the proper differentiation of NSCs, suggesting a critical role for BMP signaling. Based on the findings that BMP signaling is essential for neural differentiation and development, we propose that palmitoylation of BMP receptors regulate NSCs differentiation via modulating its downstream signaling events. We plan to identify the palmitoylation sites of the BMP receptors and the palmitoyl acyltransferases that are responsible for the modification; study the function of BMP receptor palmitoylation in NSCs self-renewal and differentiation as well as in activation of the canonical and non-canonical pathways; determine which BMP signaling pathway is involved in regulating NSCs differentiation, and by what mechanisms that palmitoylation regulates the downstream BMP signaling pathways. The results from this study will not only help us to understand the NSCs biology, providing theoretical basis for the application of NSCs in disease treatment, but also will shed light on how BMP signaling might regulate the development of other cells and tissues.

神经干细胞在神经系统的发育和损伤修复中发挥着重要作用。蛋白质的棕榈酰化修饰调节蛋白的稳定性、细胞内定位及蛋白之间的相互作用，进一步影响细胞的增殖与分化。我们的预实验结果发现抑制棕榈酰化酶可改变NSCs的分化，初步结果显示这是由于BMP受体的棕榈酰化及其下游信号通路的改变引起。在此基础上，我们拟进一步确定BMP受体的棕榈酰化位点及其修饰的棕榈酰转移酶。在BMP受体缺失的（-/-） NSCs中表达正常和棕榈酰化位点突变的BMP受体，研究其对NSCs自我更新和分化以及信号通路的影响，并knock down相应的棕榈酰转移酶进行验证。最后确定BMPR棕榈酰化调节下游信号通路的机制。本研究旨在阐明BMP受体棕榈酰化调节NSCs分化的信号通路及相应的生物学意义,有助于加深对NSCs及神经发育的理解,为NSCs在神经系统相关疾病中的应用提供理论依据，也为BMPs在其它组织中的作用机制研究提供线索。

BMP信号通路在NSC发育中有重要的调节作用，但其作用机制尚不清楚。蛋白质的翻译后修饰及动态相互作用是调控细胞增殖和分化的关键。我们研究了棕榈酰化对NSC分化的作用和分子机制。研究发现棕榈酰化能够促进NSC的分化，并且可能是通过影响BMP非经典通路的ERK的活化而发挥作用的。我们进一步的研究发现BMPRIA和BMPRII上都棕榈酰化位点的存在，这也进一步证实了BMP受体的棕榈酰化在NSC分化中起非常重要的作用。我们的研究还发现棕榈酰化可能是通过调节p53、Atm等蛋白的激活参与了DNA损伤应激反应。这些研究揭示了棕榈酰化在神经发育和DNA损伤应激反应中的重要作用。