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：
8003286
负责人：
ULUPI S JHALA
金额：
$ 10万
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：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8003286
关键词：
Acceleration Address Agonist Amino Acid Sequence Animal Model Apoptosis Apoptotic Area Aspartic Acid Autoimmune Process BAX gene Beta Cell Biological Cell Death Cellular Stress Ceramides Cessation of life DNA Diabetes Mellitus Dominant-Negative Mutation Etiology Event Family Genetic Glossary Grant Hand Inbred NOD Mice Infiltration Insulin Insulin Receptor Insulin-Dependent Diabetes Mellitus Interleukin-1 JNK-activating protein kinase Lead Leucine Zippers Leukocytes Link MAP Kinase Kinase Kinase MAPK8 gene Maps Mediating Mitochondria Mitogen-Activated Protein Kinase Kinases Mitogens Modeling Molecular Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathway interactions Peptide Sequence Determination Peptides Phosphorylation Phosphotransferases Play Polyubiquitination Post-Translational Protein Processing Predisposition Proline Proteins Proto-Oncogene Proteins c-akt Reactive Oxygen Species Regulation Research Role Serine Signal Transduction Site Stimulus Stress Structure of beta Cell of islet TNF gene Terminology Therapeutic Intervention Threonine Time Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Necrosis Factor-alpha Tumor Necrosis Factors Ubiquitin Ubiquitination attenuation base cytokine db/db mouse diabetic human NOS2A protein inhibitor/antagonist islet mixed lineage kinase 3 multicatalytic endopeptidase complex 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）：通过凋亡减少β细胞质量，代表了1型和2型糖尿病的表现中的关键转折点。 β细胞死亡的分子基础尚不清楚，并且仍然是一个强烈的研究领域。虽然几个独立的触发器可以启动死亡途径，但在大多数情况下，需要重力激酶JNK的激活才能使β细胞凋亡。同时，还需要抑制抗凋亡Akt激酶和其他Proservival途径才能加速凋亡。在β单元中，应力激酶途径在由MAPKKK，MAPKK和JNK组成的三层模块中执行。属于不同家族的多个MAPKK的存在掩盖了我们对包括细胞因子，氧化应激，DNA和紫外线损伤在内的各种刺激的理解，从而通过特定MKKK的参与导致高度特定的反应。此外，凋亡途径的高复杂性和冗余水平使JNK途径的下游效应子识别出更具挑战性的识别。在这种情况下，识别激活/Sβ细胞凋亡的关键引发剂激酶将为治疗干预提供明确而有吸引力的靶标。我们最近发现，细胞因子上调胰腺β细胞中的表达混合谱系激酶（MLK）。本赠款中要解决的具体目的包括1）使用1型和2型糖尿病的动物模型证明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。