Stil基因表达及Shh信号传导对多巴胺类细胞的保护和再生作用机制研究

帕金森氏病（PD）是一种多发于老龄人群中的由于脑部黑质多巴胺类（DA）细胞逐渐凋亡而导致的退行性中枢神经系统疾病。由于该疾病的复杂性，截止目前，其分子遗传学机制尚不明了。前期工作中，我们在斑马鱼个体中筛选到一例对多巴胺类细胞有特异影响的显性突变基因nbb。该基因的缺陷导致DA细胞凋亡。分子克隆和序列分析表明，nbb是人类致癌基因Stil的同源基因。Stil在所有脊椎动物中高度保守，并通过Shh 信号通路调节细胞的分化、增殖、以及中枢神经系统发育。本研究中，我们将利用转基因斑马鱼动物模型和大鼠PC12细胞，深入探讨Stil经Shh信号通路对DA细胞存活和再生的调控作用机制。本研究的科学价值和临床指导意义包括：1）阐述人类 Stil对DA神经细胞的保护作用，2）验证Stil在诊断和治疗PD过程中的作用机制。最终，我们的实验结果将有助于PD的基础和转化医学研究，为提高人类健康水平做出重要贡献。

Parkinson’s disease (PD) is caused by degeneration of dopaminergic (DA) neurons in the basal ganglia of the brain due to aging, environmental toxicity, or inheritance of gene mutations. Yet, the underlying molecular genetic mechanisms are unclear. Previously, we isolated a zebrafish mutation (night blindness b; nbb) that is suitable for PD research. Molecular cloning of nbb revealed that nbb is a homolog of the human oncogene SCL/TAL1 interrupting locus (Stil). Stil encodes a 143-KD protein, which is highly conserved in all vertebrate species. In mammals, Stil regulates neural development through the Sonic hedgehog (Shh) pathway. In humans, the expression of Stil is involved in cancer cell differentiation and proliferation, and mutations in Stil cause abnormal brain system development. Considering the conserved roles of Stil in different species and cell types, the function of Stil expression in DA cell proliferation and neural protection, and the effect of Shh signaling in modulation of neural toxic susceptibility, we propose that Stil may function as a tool for therapeutic treatments of degenerative neurological diseases, such as PD. Recently, we generated several DA-specific transgenic zebrafish lines that are suitable for PD studies. In this research, using the transgenic lines, we will study the novel functions of Stil in the Shh pathway in DA cells (i.e., degeneration, survival, and regeneration). The significance of this research is two-fold: First, it will elucidate the novel function of the human oncogene Stil in neural protection. Second, it will provide proof-of-concept that Stil can be developed as a tool for studying and therapeutic treatments of PD. As such, the proposed research will have broad impacts on human health.