Cytoprotective Effects of UPR Modulators in ER Stress-Challenged beta-Cells

UPR 调节剂对 ER 应激挑战的 β 细胞的细胞保护作用

基本信息

批准号：
7943451
负责人：
Bradley J Backes
金额：
$ 2.87万
依托单位：
METAFOLD THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-10 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943451
关键词：
Affect American Animal Model Apoptosis Apoptotic Beta Cell Biochemical Biological Assay Bypass Cell Death Cell Line Cell Survival Cell physiology Cells Cellular Assay Collection Cytoprotection Cytoprotective Agent Data Development Disease Disease Progression Endoplasmic Reticulum Engineering Face Funding Generations Genes Glucose Goals Healthcare Homeostasis Homology Modeling Human In Vitro Individual Insulin Insulin Resistance Integral Membrane Protein Islets of Langerhans JNK-activating protein kinase JUN gene Lead Libraries Ligands Link Longevity MAPK8 gene Mammalian Cell Messenger RNA Molecular Non-Insulin-Dependent Diabetes Mellitus Oral Organism Output Pathway interactions Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Productivity Proteins Publishing RNA Processing RNA Splicing Rattus Ribonucleases Role Screening procedure Signal Pathway Signal Transduction Small Business Technology Transfer Research Stress Structure Structure-Activity Relationship Therapeutic Translations Upper arm Variant base cost cytotoxic design diabetic endoplasmic reticulum stress glycemic control high throughput screening improved inhibitor/antagonist insulin secretion insulinoma kinase inhibitor lead series novel prevent programs protein folding protein structure response scaffold small molecule

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance; frank disease develops when approximately 50% of insulin-producing pancreatic islet ¿-cells of affected individuals undergo cell death. Numerous recent studies link T2D to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in ¿-cells, to ¿-cell apoptosis, and to general peripheral insulin resistance, all hallmarks of T2D. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that a key component of the UPR, Ire1a, acts as a toggling switch between homeostatic and apoptotic outputs, ultimately controlling ¿-cell fate. The project goal of this STTR is to identify a small molecule that biases Ire1a.s outputs towards homeostasis and evaluate its therapeutic potential by demonstrating cytoprotective effects in ¿-cell-derived cell lines. We have developed a novel biochemical assay to detect such compounds, with hits already identified. Structure-based design will guide our medicinal chemistry to provide increasingly potent cytoprotective agents. Results from the proposed studies will guide our selection of lead compounds to validate this approach in disease-relevant animal models of ¿-cell function and capacity. Ultimately, these studies represent significant early steps to develop a novel, oral treatment for the improvement of glycemic control in type 2 diabetics with the unique potential to modify disease progression.

描述（由申请人提供）：2 型糖尿病 (T2D) 影响着 1800 万美国人，每年造成的国家医疗保健和生产力损失超过 1000 亿美元，当大约 50% 的人出现代偿性胰岛素抵抗时，T2D 就开始出现。产生胰岛素的胰岛 ¿最近的许多研究将 T2D 与内质网 (ER) 应激联系起来，当蛋白质折叠需求超过分泌途径中的蛋白质折叠能力时就会发生这种情况。值得注意的是，越来越多的证据表明 ER 应激会导致这种情况。减少葡萄糖反应性胰岛素分泌 ¿ -细胞，至 ¿细胞凋亡和一般外周胰岛素抵抗，T2D 的所有特征都会触发未折叠蛋白反应 (UPR) 途径，如果体内稳态未通过这些途径恢复，该途径会减慢翻译并转录上调增强 ER 蛋白折叠能力的基因。相反，UPR 会触发细胞凋亡，而 UPR 的关键成分 Ire1a 充当稳态和细胞凋亡输出之间的切换开关，最终控制细胞凋亡。 ¿该 STTR 的项目目标是鉴定一种使 Ire1a.s 输出偏向稳态的小分子，并通过展示 ¿ 中的细胞保护作用来评估其治疗潜力。 -细胞衍生的细胞系。我们开发了一种新的生化检测方法来检测此类化合物，基于结构的设计将指导我们的药物化学提供越来越有效的细胞保护剂。先导化合物在疾病相关动物模型中验证这种方法最终，这些研究代表了开发一种新型口服治疗方法的重要早期步骤，该治疗方法可改善 2 型糖尿病患者的血糖控制，具有改变疾病进展的独特潜力。