The role of sphingolipids in the pancreatic beta cell

最近的研究表明，鞘磷脂可能在人的生存和功能中起着重要的调节作用。 胰岛β细胞。神经酰胺，是对炎性细胞因子(如肿瘤)的反应而产生的 肿瘤坏死因子-α(TNF-α)、白介素1等，已被证明可诱导β细胞凋亡和 抑制胰岛素分泌。神经节苷脂是神经酰胺的糖基化形式，是推测的自身抗原。 参与了胰岛素炎和1型糖尿病的诱发。和，鞘氨醇1-磷酸，其衍生物 神经酰胺是由各种生长因子产生的，已被证明可以促进β细胞的生存和生长， 也许是通过对抗其前体神经酰胺的作用。尽管有这些孤立的研究，但 鞘磷脂作为β细胞生长、增殖和功能的调节剂还没有详细的研究， 无论是在分离的细胞中还是在完整的动物中。在此，我们建议启动研究，研究 神经鞘脂在β细胞功能中的作用。首先，使用药物抑制剂和一种新型的基因敲除小鼠 不能制造神经酰胺，我们将确定调节鞘磷脂水平对 啮齿动物体内的β细胞功能。第二，我们将研究神经酰胺通过的分子机制 而1-磷酸鞘氨醇则以不同的方式调节细胞的存活，同时评估两者之一的作用。 细胞因子或游离脂肪酸引起的细胞死亡的调节剂。最终，这些研究将有助于揭示 调节β细胞鞘脂水平是否有利于阻止β细胞死亡 移植或预防1型或2型糖尿病的发病。

Recent studies suggest that sphingolipids may have important regulatory roles in the survival and function of pancreatic beta-cells. Ceramides, which are produced in response to inflammatory cytokines (e.g. tumor necrosis factor-alpha (TNF-alpha), interleukin 1, etc.), have been shown to induce beta-cell apoptosis and inhibit insulin secretion. Gangliosides, which are glycosylated forms of ceramide, are putative autoantigens involved in the induction of insulitis and type 1 diabetes. And, sphingosine 1-phosphate, a derivative of ceramide produced by various growth factors, has been shown to promote beta-cell survival and growth, perhaps by opposing effects of its precursor, ceramide. Despite these isolated studies, the importance of sphingolipids as regulators of beta-cell growth, proliferation, and function has not been studied in detail, either in isolated cells or in intact animals. Herein we propose to initiate studies investigating the role of sphingolipids in beta-cell function. First, using pharmacological inhibitors and a novel knockout mouse that is incapable of making ceramides, we will determine the consequence of modulating sphingolipid levels on beta cell function in rodents. Second, we will investigate the molecular mechanisms through which ceramide and sphingosine 1-phosphate serve to divergently regulate cell survival, while evaluating the role of either as a modulator of cytokine or free fatty acid-induced cell death. Ultimately these studies will help reveal whether modulating beta-cell sphingolipid levels is beneficial for either blocking beta-cell death during transplantation or preventing the onset of type 1 or type 2 diabetes.