Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation

性状（由申请方提供）：脂肪源性分泌因子脂联素促进神经酰胺catalysts的增加，其依赖于脂联素受体1和2。受体相关的神经酰胺酶活性促进神经酰胺降解和1-磷酸鞘氨醇（S1 P）的产生，为b细胞提供保护，使其免受caspase-8依赖性促凋亡损伤。神经酰胺向S1 P的简单两步转化以及两种脂质对细胞存活和增殖的截然相反的作用使我们和其他人假设存在由这两种脂质控制的细胞变阻器。由于脂联素促进全身代谢的改善，目前尚不清楚脂联素在b细胞内的局部作用是否引起这些保护作用，或者是否循环代谢环境的改善介导了这些保护反应。了解这种保护机制对于制定策略以维持个体中健康的b细胞群至关重要。我推测脂联素受体通过调节神经酰胺：S1 P的比例来促进B细胞的存活和增殖。在这里，我将评估b细胞特异性过表达脂联素受体或酸性神经酰胺酶（假定阳性对照）对维持功能性b细胞群的影响。此外，我将检查的贡献S1 P介导的保护作用对b细胞的生存在小鼠缺乏S1 P受体（1，2或3）或小鼠过表达的S1 P降解酶S1 P裂解酶。为了做到这一点，我将利用“PANIC-ATTAC”转基因小鼠，它提供可诱导的，可滴定的，b细胞特异性凋亡。由于I通过轻度凋亡而不是坏死来功能性地抑制b细胞，因此I减少了b细胞死亡的促炎成分，因此在停止二聚化剂处理后，b细胞群可以重建。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对以下方面的影响：a）脂联素介导的b细胞抗凋亡作用，和B）脂联素增强功能性b细胞团再生潜力的能力。我还将使用ob/ob小鼠作为糖尿病b细胞衰竭模型，确定脂联素受体1、脂联素受体2或酸性神经酰胺酶（AC）的b细胞特异性过表达是否足以维持功能性胰岛质量。这些研究将有望通过促进b细胞功能和促进b细胞群内的再生过程，为治疗和预防糖尿病提出新的治疗途径。

DESCRIPTION (provided by applicant): 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 b-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 b-cell elicit these protective effects, or if improvements in the circulaing metabolic milieu mediate these protective responses. Understanding this protective mechanism is critical for developing strategies to maintain healthy populations of b-cells in individuals. I hypothesize that adiponectin receptors promote b-cell survival and proliferation by governing the ceramide:S1P ratio. Here, I will evaluate the effects of b-cell-specific overexpression of adiponectin receptors or acid ceramidase (a presumed positive control) on the maintenance of functional b-cell mass. Moreover, I will examine the contributions of S1P-mediated protective effects on b-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, b-cell specific apoptosis. Since I functionaly inactivate the b-cells through mild apoptosis as opposed to necrosis, I reduce the pro-inflammatory component of b-cell death, and thus b-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 b-cell, and b) adiponectin's ability to enhance the regenerative potential of functional b-cell mass. I will also determine if b-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 b-cell failure. These studies will hopefully suggest novel therapeutic avenues for the treatment and prevention of diabetes by promoting b-cell functionality, and by promoting regenerative processes within the b-cell population.