Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation

描述（由申请人提供）：脂肪衍生分泌因子脂联素促进神经酰胺分解代谢的增加，这依赖于脂联素受体1和2。受体相关的神经酰胺酶活性促进神经酰胺降解和鞘氨醇1-磷酸（S1P）的产生，为b细胞提供保护，免受caspase-8依赖性的促凋亡损伤。神经酰胺到S1P的简单两步转化，以及这两种脂质在细胞存活和增殖中截然相反的作用，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。由于脂联素促进了全身代谢的改善，目前尚不清楚是b细胞内脂联素的局部作用引起了这些保护作用，还是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维持个体健康b细胞群的策略至关重要。我假设脂联素受体通过调控神经酰胺：S1P比值促进b细胞存活和增殖。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（假定为阳性对照）对维持功能性b细胞质量的影响。此外，我将研究在缺乏S1P受体（1、2或3）或S1P降解酶S1P裂解酶过表达的小鼠中，S1P介导的保护作用对b细胞存活的贡献。为了做到这一点，我将利用“PANIC-ATTAC”转基因小鼠，它提供了诱导的，可滴定的，b细胞特异性凋亡。由于我通过轻度凋亡而不是坏死来功能性地灭活b细胞，我减少了b细胞死亡的促炎成分，因此b细胞团块可以在停止二聚体治疗后重建。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S1P对以下方面的影响：a)脂联素介导的b细胞抗凋亡作用，b)脂联素增强功能性b细胞群再生潜力的能力。我还将确定b细胞特异性过表达脂联素受体1、脂联素受体2或酸性神经酰胺酶（AC）是否足以维持功能性胰岛质量，使用ob/ob小鼠作为糖尿病b细胞衰竭的模型。这些研究有望通过促进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供新的治疗途径。

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. PUBLIC HEALTH RELEVANCE: Understanding the protective mechanisms by which adiponectin maintains functional b-cell mass is critical for developing strategies to maintain healthy populations of b-cells in individuals. These studies may suggest novel therapies for the treatment and prevention of diabetes by promoting functional b-cell mass, and potential regenerative processes within the b-cell. Moreover, they will enhance the general understanding of factors governing cell survival and proliferation, which has implications for a diverse array of diseases and treatment modalities influenced by cell death.