Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation

脂联素受体和 S1P 信号在 Beta 细胞存活和增殖中的作用

基本信息

批准号：
8889773
负责人：
WILLIAM L HOLLAND
金额：
$ 24.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889773
关键词：
Adipose tissue Apoptosis Apoptotic Beta Cell Carbohydrates Catabolism Cell Death Cell Proliferation Cell Survival Cells Ceramidase Ceramides Cytoprotection Diabetes Mellitus Diabetes prevention Disease Enzymes Exercise Failure Fatty acid glycerol esters Figs - dietary Generations Glucose Individual Inflammatory Insulin Islets of Langerhans Transplantation Learning Leptin Lipids Liver Maintenance Mediating Mentors Metabolic Metabolism Modality Modeling Mus Natural regeneration Necrosis Nutrient Palmitates Pancreas Phase Population Predisposition Prevention Process Production Recovery of Function Response Elements Role Signal Transduction Skeletal Muscle Sphingosine-1-Phosphate Receptor Stimulus Tetracyclines Tissues Transgenes Transgenic Mice Transgenic Organisms Transplantation abstracting adiponectin caspase-8 diabetic galactosylgalactosylglucosylceramidase insulin secretion islet novel novel therapeutics overexpression peptide hormone protective effect receptor reconstitution regenerative response sphingosine 1-phosphate sphingosine-1-phosphate lyase uptake

项目摘要

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.

抽象的脂肪源性分泌因子脂联素促进神经酰胺分解代谢的增加，这是依赖于脂联素受体 1 和 2。受体相关的神经酰胺酶活性可促进神经酰胺 1-磷酸鞘氨醇 (S1P) 的降解和生成，为  细胞提供免受 caspase-8- 侵害的保护神经酰胺向 S1P 的简单两步转化以及完全相反的作用。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于脂联素促进全身新陈代谢的改善，因此变阻器由这两种脂质控制。目前尚不清楚脂联素在  细胞内的局部作用是否会引起这些保护作用，或者是否循环代谢环境的改善介导了这些保护性反应。保护机制对于制定维持健康的  细胞群策略至关重要我研究发现脂联素受体通过控制 β 细胞的存活和增殖。在这里，我将评估脂联素受体的细胞特异性过度表达的影响。或酸性神经酰胺酶（假定的阳性对照）对维持功能性细胞量的作用。将检查 S1P 介导的保护作用对缺乏 S1P 的小鼠中  细胞存活的贡献受体（1、2 或 3）或过度表达 S1P 降解酶 S1P 裂合酶的小鼠。为此，我将利用“PANIC-ATTAC”转基因小鼠，它提供可诱导的、可滴定的  细胞特异性凋亡，因为我通过轻度凋亡使  细胞功能失活。与坏死相反，我减少了细胞死亡的促炎成分，因此细胞团可以总的来说，我将能够评估脂联素、脂联素受体、酸性神经酰胺酶和 S1P 对：a) 脂联素介导的抗凋亡作用 b) 脂联素增强功能性  细胞再生潜力的能力我还将确定脂联素受体 1、脂联素受体 2 是否存在  细胞特异性过度表达。或酸性神经酰胺酶（AC）足以使用 ob/ob 小鼠作为模型维持功能性胰岛质量糖尿病细胞衰竭。这些研究有望为治疗和预防疾病提供新的治疗途径通过促进  细胞功能和促进  细胞内的再生过程来治疗糖尿病人口。