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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.

摘要