Role of Sphingomyelin-Ceramide Cycle as a Signaling Pathway in Pediatric Diseases

酸性鞘磷脂酶作为细胞内信号分子，在氧化应激诱导的细胞反应中产生神经酰胺起重要作用。我们的研究提示了氧化应激、x射线、过氧化氢和紫外线激活酸性鞘磷脂酶的分子机制。酸性鞘磷脂酶可能通过酶的c端半胱氨酸残基的氧化变化而被激活。这种变化使酶被激活并移动到富含鞘磷脂的质膜上，产生神经酰胺，引发氧化应激诱导的细胞反应。这一结果表明，酸性鞘磷脂酶可能成为一些氧化应激相关疾病的新疗法的分子靶点。接下来，我们揭示了酸性鞘磷脂酶缺乏症培养细胞的表型和基因型以及酶活性和细胞内胆固醇储存之间的一些关系。此外，我们试图确定一个负责基因和Costello综合征的发病机制。

Acid sphingomyelinase plays an important role in oxidative stress-induced cellular responses to generate ceramide as an intracellular signaling molecule. Our study suggested a molecular mechanism for activation of acid sphingomyelinase by oxidative stress, X-ray, hydrogen peroxide, and UV. Acid sphingomyelinase may be activated through an oxidative change of C-terminus cysteine residue of the enzyme. The change makes the enzyme to be activated and move to sphingomyelin-rich plasma membrane and generates ceramide, triggering oxidative stress-induced cellular responses. This result demonstrated that acid sphingomyelinase could be a molecular target to create novel treatments of some oxidative stress-related diseases. Next, we revealed some relations between phenotypes and genotypes and between enzyme activity and intracellular cholesterol storage in culture cells of acid sphingomyelinase deficient disease. In addition, we attempted to determine a responsible gene and pathogenesis of Costello syndrome.