Mechanisms of Pancreatic Beta Cell Dysfunction

胰腺β细胞功能障碍的机制

基本信息

批准号：
10214598
负责人：
ULUPI S JHALA
金额：
$ 38.75万
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：
2018
资助国家：
美国
起止时间：
2018-07-10 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214598
关键词：
Ablation Address Apoptosis Ascorbic Acid Attenuated Beta Cell Binding Biochemical Calcium Cell Death Cell Survival Communication Data Deubiquitination Development Diabetes Mellitus Disease Electron Microscopy Elements Equilibrium Family Financial cost Functional disorder Future GRP75 Glean Grant Human Hyperglycemia In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Insulin Insulin-Dependent Diabetes Mellitus Interleukin-1 beta Knockout Mice Label Lead MAPK8 gene Mass Spectrum Analysis Mediating Membrane Membrane Microdomains Mitochondria Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Pattern Peroxidases Phosphotransferases Play Predisposition Protein-Serine-Threonine Kinases Proteins Quality Control Regulation Research Resistance Role Signal Transduction Stimulus Streptozocin Structure Structure of beta Cell of islet Techniques attenuation autocrine cytokine cytotoxic endoplasmic reticulum stress genetic variant glucose analog in vivo inorganic phosphate insight islet macrophage novel recruit response scaffold

项目摘要

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. The Tribbles-family of pseudokinases have been strongly implicated in the regulation of inflammatory pathways. 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 in addition to its role in ER stress, TRB3 is contributes to compromise in mitochondrial quality control and integrity. Both mechanisms together likely contribute to susceptibility of beta cell to proapoptotic stimuli. In this application, we will further define examine molecular mechanisms that enable TRB3-mediated fine tuning of beta cell survival and death. We propose the following specific aims: 1) Examine how mice with whole body and beta cell-specific loss of TRB3, response to induced diabetes. 2) Examine the role of TRB3 interacting proteins in augmenting inflammation. 3) Explore the role of TRB3 in ER-mitochondrial crosstalk.

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，细胞因子的组合触发β细胞炎症最终导致β细胞凋亡。伪动酶的trag子植物与炎症途径的调节有着强烈的影响。我们将研究工作集中在理解调节β细胞炎症发展的信号传导机制上，发现假酶TRB3在增强导致细胞死亡的机制中起关键作用。我们发现，除了其在ER应力中的作用外，TRB3还有助于在线粒体质量控制和完整性中妥协。这两种机制融合都可能导致β细胞对促凋亡刺激的敏感性。在此应用中，我们将进一步定义检查beta细胞存活和死亡的TRB3介导的微调的分子机制。我们提出以下特定目的：1）检查TRB3的全身和β细胞特异性损失的小鼠如何反应诱导的糖尿病。 2）检查TRB3相互作用蛋白在增加炎症中的作用。 3）探索TRB3在ER-线粒体串扰中的作用。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stress-induced pseudokinase TRB3 augments IL1β signaling by interacting with Flightless homolog 1.

DOI：
10.1016/j.jbc.2023.104803
发表时间：
2023-08
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Gonuguntla, Sumati;Humphrey, Rohan K.;Gorantla, Akshita;Hao, Ergeng;Jhala, Ulupi S.
通讯作者：
Jhala, Ulupi S.