The role of sphingolipids in the pancreatic beta cell

描述(申请人提供)：最近的研究表明，鞘磷脂可能在胰岛β细胞的生存和功能中起着重要的调节作用。神经酰胺是在炎性细胞因子(如肿瘤坏死因子-α、白介素1等)作用下产生的，具有诱导β细胞凋亡和抑制胰岛素分泌的作用。神经节苷脂是神经酰胺的糖基化形式，是可能参与诱导胰岛素炎和1型糖尿病的自身抗原。此外，1-磷酸鞘氨醇，一种由各种生长因子产生的神经酰胺的衍生物，已经被证明可以促进β细胞的生存和生长，可能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，但无论是在分离的细胞中还是在完整的动物中，鞘脂作为β细胞生长、增殖和功能调节因子的重要性都没有得到详细的研究。在此，我们建议开始研究鞘磷脂在β细胞功能中的作用。首先，使用药物抑制剂和一种新型的不能制造神经酰胺的基因敲除小鼠，我们将确定调节鞘磷脂水平对啮齿动物β细胞功能的影响。其次，我们将研究神经酰胺和1-磷酸鞘氨醇不同地调节细胞存活的分子机制，同时评估它们作为细胞因子调节剂或游离脂肪酸诱导的细胞死亡的作用。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移植过程中的β细胞死亡或预防1型或2型糖尿病的发病。

DESCRIPTION (provided by applicant): 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.