The role of sphingolipids in the pancreatic beta cell

描述（由申请人提供）：最近的研究表明，鞘脂可能对胰腺β细胞的存活和功能具有重要的调节作用。神经酰胺，其响应于炎性细胞因子（例如肿瘤坏死因子-α（TNF-α）、白细胞介素1等）而产生，已显示诱导β细胞凋亡并抑制胰岛素分泌。神经节苷脂是神经酰胺的糖基化形式，是参与诱导胰岛炎和1型糖尿病的假定自身抗原。而且，鞘氨醇1-磷酸，一种由各种生长因子产生的神经酰胺衍生物，已被证明可以促进β细胞的存活和生长，这可能是通过其前体神经酰胺的相反作用。尽管有这些孤立的研究，鞘脂作为β-细胞生长，增殖和功能的调节剂的重要性尚未在分离的细胞或完整的动物中详细研究。在此，我们建议启动研究鞘脂在β细胞功能中的作用。首先，使用药理学抑制剂和一种不能产生神经酰胺的新型基因敲除小鼠，我们将确定调节鞘脂水平对啮齿动物β细胞功能的影响。其次，我们将研究神经酰胺和鞘氨醇1-磷酸盐的分子机制，通过这些机制，神经酰胺和鞘氨醇1-磷酸盐用于不同的调节细胞存活，同时评估作为细胞因子或游离脂肪酸诱导的细胞死亡的调节剂的作用。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型糖尿病的发生。

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.