Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation

摘要 脂肪源性分泌因子脂联素促进神经酰胺catenin的增加， 依赖于脂联素受体1和2。受体相关神经酰胺酶活性促进神经酰胺 鞘氨醇1-磷酸（S1 P）的降解和产生，为乳腺癌细胞提供保护，使其免受半胱天冬酶-8- 依赖性促凋亡损伤。神经酰胺简单的两步转化为S1 P和完全相反的作用 这两种脂质对细胞存活和增殖的影响使我们和其他人假设存在一种细胞 由这两种脂质控制的变阻器。由于脂联素促进全身代谢的改善， 脂联素在胰岛细胞内的局部作用是否引起这些保护作用， 循环代谢环境的改善介导了这些保护性反应。理解这一 保护机制对于发展维持健康的胰岛细胞群的策略至关重要。 个体我推测脂联素受体通过调节细胞内的蛋白质， 神经酰胺：S1 P比率。在这里，我将评估脂联素受体的胰岛细胞特异性过表达的影响， 或酸性神经酰胺酶（假定阳性对照）对维持功能性神经胶质瘤细胞质量的影响。而且我 将研究S1 P介导的保护作用对缺乏S1 P的小鼠的胰岛细胞存活的影响 受体（1、2或3）或过表达S1 P降解酶S1 P裂解酶的小鼠。 为了做到这一点，我将利用“PANIC-ATTAC”转基因小鼠，它提供了诱导， 可滴定的，可滴定的细胞特异性凋亡。由于我通过轻度凋亡功能性地抑制了凋亡细胞， 与坏死相反，I减少了炎性细胞死亡的促炎成分，因此炎性细胞团可以被 在停止二聚化器处理后重构。总的来说，我将能够评估 脂联素、脂联素受体、酸性神经酰胺酶和S1 P对：a）脂联素介导的抗凋亡 在β细胞中的作用，以及B）脂联素增强功能性β细胞再生潜力的能力 马萨诸塞州我还将确定脂联素受体1，脂联素受体2， 或酸性神经酰胺酶（AC）足以维持功能性胰岛质量， 糖尿病性胰岛细胞衰竭。 这些研究将有望为治疗和预防 通过促进胰岛细胞的功能，并通过促进胰岛细胞内的再生过程， 人口

Abstract The adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism, which is dependent on adiponectin receptors 1 and 2. The receptor-associated ceramidase activity promotes ceramide degradation and generation of sphingosine 1-phosphate (S1P), offering cells protection from caspase-8- dependent pro-apoptotic insults. The simple 2-step conversion of ceramide to S1P and starkly opposing roles of the two lipids on cell survival and proliferation has led us and others to postulate the existence of a cellular rheostat governed by these two lipids. As adiponectin promotes improvements in whole body metabolism, it remains unclear whether the local actions of adiponectin within the cell elicit these protective effects, or if improvements in the circulating metabolic milieu mediate these protective responses. Understanding this protective mechanism is critical for developing strategies to maintain healthy populations of -cells in individuals. I hypothesize that adiponectin receptors promote -cell survival and proliferation by governing the ceramide:S1P ratio. Here, I will evaluate the effects of cell-specific overexpression of adiponectin receptors or acid ceramidase (a presumed positive control) on the maintenance of functional cell mass. Moreover, I will examine the contributions of S1P-mediated protective effects on -cell survival in mice lacking S1P receptors (1, 2 or 3) or mice overexpressing the S1P degrading enzyme S1P lyase. To do that, I will take advantage of the “PANIC-ATTAC” transgenic mouse, which offers inducible, titratable, cell specific apoptosis. Since I functionally inactivate the cells through mild apoptosis as opposed to necrosis, I reduce the pro-inflammatory component of cell death, and thus cell mass can be reconstituted upon cessation of dimerizer treatment. Collectively, I will be able to evaluate the effects of adiponectin, adiponectin receptors, acid ceramidase, and S1P on: a) the adiponectin-mediated anti-apoptotic actions in the -cell, and b) adiponectin's ability to enhance the regenerative potential of functional cell mass. I will also determine if -cell-specific overexpression of adiponectin receptor 1, adiponectin receptor 2, or acid ceramidase (AC) is sufficient to maintain functional islet mass using the ob/ob mouse as a model of diabetic -cell failure. These studies will hopefully suggest novel therapeutic avenues for the treatment and prevention of diabetes by promoting -cell functionality, and by promoting regenerative processes within the -cell population.