Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation

描述(申请人提供)：脂肪来源的分泌因子脂联素促进神经酰胺分解代谢增加，这依赖于脂联素受体1和2。受体相关神经酰胺酶活性促进神经酰胺降解和1-磷酸鞘氨醇(S1P)的产生，保护b细胞免受caspase-8依赖的促凋亡损伤。神经酰胺简单的两步转化为S1P，以及这两种脂类对细胞生存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类控制的细胞变阻器。由于脂联素促进全身新陈代谢的改善，目前尚不清楚脂联素在b细胞内的局部作用是否引起了这些保护作用，或者循环代谢环境的改善是否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细胞群体至关重要。我假设脂联素受体通过调节神经酰胺与S1P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(假定为阳性对照)对维持功能性b细胞群的影响。此外，我将研究S1P介导的保护作用对缺乏S1P受体(1，2或3)的小鼠或过度表达S1P降解酶S1P裂解酶的小鼠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，它提供可诱导的、可滴定的b细胞特异性凋亡。由于我通过轻微的细胞凋亡而不是坏死来使b细胞失活，我减少了b细胞死亡的促炎成分，因此在停止二聚体治疗后b细胞团可以重新形成。总而言之，我将能够评估脂联素、脂联素受体、酸性神经酰胺酶和S1P在以下方面的作用：a)脂联素介导的b细胞抗凋亡作用，以及b)脂联素增强功能性b细胞团的再生潜力的能力。我还将使用肥胖/肥胖小鼠作为糖尿病b细胞衰竭的模型，确定b细胞特异性脂联素受体1、脂联素受体2或酸性神经酰胺酶(AC)的过度表达是否足以维持胰岛功能团块。这些研究有望为糖尿病的治疗和预防提供新的治疗途径，通过促进b细胞的功能，并通过促进b细胞群体内的再生过程。 公共卫生相关性：了解脂联素维持功能性b细胞群的保护机制，对于制定策略以维持个体中健康的b细胞群体至关重要。这些研究可能会为糖尿病的治疗和预防提供新的疗法，方法是促进功能性b细胞群，以及b细胞内潜在的再生过程。此外，它们将增强对控制细胞生存和增殖的因素的一般理解，这对一系列不同的 受细胞死亡影响的疾病和治疗方式。

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.