Molecular Mechanisms Regulating Beta Cell Death

调节β细胞死亡的分子机制

基本信息

批准号：
9001393
负责人：
ULUPI S JHALA
金额：
$ 15.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9001393
关键词：
AKT inhibition Address Affinity Apoptosis Beta Cell Binding Biochemical Biological Calcium Cell Death Cell Line Cell Survival Ceramides Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Cytokine Signaling Data Development Diabetes Mellitus Disease Equilibrium Event Fatty Acids Financial cost Functional disorder Future GRP75 Generations Grant Health Helper-Inducer T-Lymphocyte Homologous Gene Human Hyperglycemia Inflammation Inflammatory Inflammatory Response Insulin Insulin-Dependent Diabetes Mellitus Interleukin-1 Lead Lipids MAPK8 gene Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Membrane Microdomains Mitochondria Molecular Mus Mutation Pathway interactions Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Predisposition Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Receptor Signaling Relative (related person)Reporting Research Resistance Role Signal Pathway Signal Transduction Sphingolipids Stimulus Stress Structure of beta Cell of islet Technology Time attenuation cytokine inorganic phosphate islet novel palmitoylation scaffold type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Pancreatic beta cell death marks a critical turning point in the development of diabetes. In type 1 diabetes, a combination of cytokines trigger beta cell inflammation ultimately leading to beta cell apoptosis. We have focused our research efforts on understanding signaling mechanisms that modulate the progression of beta cell inflammation and found that the pseudokinase TRB3 plays a key role in augmenting mechanisms that lead to cell death. We find that TRB3 is instrumental in compromising mitochondrial integrity while others have reported a role for TRB3 in ER stress. Both mechanisms likely contribute to susceptibility of beta cell to proapoptotic stimuli. TRB3 has been characterized as a negative regulator of AKT, a prosurvival kinase that is indispensible for the survival and normal funtioning of the beta cell. We provide preliminary data to suggest that beyond AKT, TRB3 also modulates the function of several inflammatory proteins in the beta cell. In this grant we will further defin examine molecular mechanisms that enable TRB3-mediated fine tuning of beta cell survival and death. We propose the following specific aims: 1) Elucidate the mechanism by which TRB3 modulates inflammatory signaling 2) Explore the role of TRB3 in ER-mitochondrial crosstalk and 3) Examine how post-translational modifications alter the biological role of TRB3 in beta cells.

描述（由申请人提供）：胰腺β细胞死亡标志着糖尿病发展的关键转折点。在 1 型糖尿病中，细胞因子的组合会引发 β 细胞炎症，最终导致 β 细胞凋亡。我们的研究重点是了解调节 β 细胞炎症进展的信号传导机制，并发现假激酶 TRB3 在增强导致细胞死亡的机制中发挥着关键作用。我们发现 TRB3 在损害线粒体完整性方面发挥了重要作用，而其他人则报道了 TRB3 在 ER 应激中的作用。这两种机制都可能导致 β 细胞对促凋亡刺激的敏感性。 TRB3 被认为是 AKT 的负调节因子，AKT 是一种对于生存和正常功能必不可少的促生存激酶 β细胞的。我们提供的初步数据表明，除了 AKT 之外，TRB3 还调节 β 细胞中几种炎症蛋白的功能。在这笔资助中，我们将进一步定义和研究能够通过 TRB3 介导的 β 细胞存活和死亡微调的分子机制。我们提出以下具体目标：1）阐明TRB3调节炎症信号传导的机制2）探索TRB3在内质网线粒体串扰中的作用3）检查翻译后修饰如何改变TRB3在β细胞中的生物学作用。