Signaling Cascades in Regulation of Pancreatic Beta cell mass.

胰腺β细胞团调节中的信号级联。

基本信息

批准号：
8014875
负责人：
ULUPI S JHALA
金额：
$ 31.43万
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：
2008
资助国家：
美国
起止时间：
2008-02-05 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8014875
关键词：
Acceleration Address Agonist Animal Model Apoptosis Apoptotic Area Autoimmune Process BAX gene Beta Cell Biological Cell Death Cellular Stress Ceramides Cessation of life DNA Damage Diabetes Mellitus Dominant-Negative Mutation Etiology Event Family Genetic Grant Inbred NOD Mice Infiltration Insulin Insulin-Dependent Diabetes Mellitus Interferons Interleukin-1 JNK-activating protein kinase Lead Leukocytes Link MAP Kinase Kinase Kinase MAPK8 gene Maps Mediating Mitochondria Mitogen-Activated Protein Kinase Kinases Modeling Molecular Names Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathway interactions Peptides Phosphorylation Phosphotransferases Play Polyubiquitination Post-Translational Protein Processing Predisposition Principal Investigator Proto-Oncogene Proteins c-akt Regulation Research Resource Sharing Role Signal Transduction Site Stimulus Stress Structure of beta Cell of islet TNF gene Therapeutic Intervention Time Ubiquitin Ubiquitination attenuation base cytokine db/db mouse diabetic islet mixed lineage kinase 3 programs response type I and type II diabetes type I diabetic ultraviolet damage upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Decrease in beta cell mass by apoptosis represents the key turning point in the manifestation of both type 1 and type 2 diabetes. The molecular basis of beta cell death is not well understood and remains an intense area of research. While several independent triggers can initiate the death pathway, activation of the stress kinase JNK is required in most cases for apoptosis of beta cells. At the same time, the inhibition of anti-apoptotic Akt kinase and other prosurvival pathways is also required for the acceleration of apoptosis. In beta cells the stress kinase pathway is executed in a three-tiered module consisting of MAPKKK, MAPKK, and JNK. The existence of multiple MAPKKKs belonging to distinct families has obscured our understanding of how a variety of stimuli including cytokines, oxidative stress, DNA and UV damage lead to highly specific responses by the engagement of specific MKKKs. Furthermore, the high level of complexity and redundancy in apoptosis pathways has made identification of downstream effectors of the JNK pathway far more challenging. In such a situation, identifying the key initiator kinase/s that activate/s beta cell apoptosis would provide clear and attractive targets for therapeutic intervention. We have recently found that cytokines upregulate the expression mixed lineage kinases (MLKs) in pancreatic beta cells. The specific aims to be addressed in this grant include 1) Demonstration of a causal role for MLKs in induction of beta cell apoptosis using animal models of type 1 and type 2 diabetes. 2) Examine downstream molecular mechanisms by which mixed lineage kinases regulate beta cell death. 3) Examination of post-translational mechanisms that regulate the activation of MLKs in the pancreatic beta cell.

描述（由申请人提供）：细胞凋亡导致的β细胞质量减少代表了1型和2型糖尿病表现的关键转折点。 β细胞死亡的分子基础尚不清楚，仍然是一个热门的研究领域。虽然几个独立的触发因素可以启动死亡途径，但在大多数情况下，β 细胞凋亡需要激活应激激酶 JNK。同时，抑制抗凋亡Akt激酶和其他促存活途径也是细胞凋亡加速所必需的。在 β 细胞中，应激激酶通路在由 MAPKKK、MAPKK 和 JNK 组成的三层模块中执行。属于不同家族的多个 MAPKKK 的存在模糊了我们对细胞因子、氧化应激、DNA 和紫外线损伤等各种刺激如何通过特定 MKKK 的参与而导致高度特异性反应的理解。此外，细胞凋亡途径的高度复杂性和冗余性使得 JNK 途径下游效应子的识别更具挑战性。在这种情况下，识别激活β细胞凋亡的关键启动激酶将为治疗干预提供明确且有吸引力的目标。我们最近发现细胞因子上调胰腺β细胞中混合谱系激酶（MLK）的表达。本次资助的具体目标包括 1) 使用 1 型和 2 型糖尿病动物模型证明 MLK 在诱导 β 细胞凋亡中的因果作用。 2) 检查混合谱系激酶调节β细胞死亡的下游分子机制。 3) 检查调节胰腺β细胞中MLK激活的翻译后机制。