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

• 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
• 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

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.

2型糖尿病（T2 D）影响着1800万美国人，每年的国家医疗保健和生产力损失成本超过1000亿美元。2型糖尿病开始作为一个国家的补偿胰岛素抵抗;弗兰克疾病发展时，约50%的胰岛素产生胰岛细胞的影响个人经历细胞死亡。许多最近的研究将T2 D与内质网（ER）应激联系起来，内质网应激是一种每当分泌途径中蛋白质折叠需求压倒蛋白质折叠能力时发生的状况。值得注意的是，有越来越多的证据表明，ER应激有助于减少葡萄糖反应性胰岛素分泌的细胞，细胞凋亡，和一般外周胰岛素抵抗，所有的标志T2 D。ER应激触发未折叠蛋白反应（UPR）途径，其减慢翻译并转录上调增强ER蛋白折叠能力的基因。如果体内平衡没有通过这些输出恢复，UPR反而触发细胞凋亡。我们假设UPR的一个关键成分Ire 1a在稳态和凋亡输出之间起着切换开关的作用，最终控制着细胞的命运。该STTR的项目目标是确定一种使Ire1a.s输出偏向稳态的小分子，并通过在细胞衍生的细胞系中证明细胞保护作用来评估其治疗潜力。我们已经开发了一种新的生化检测方法来检测这些化合物，并已经确定了命中。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。拟议研究的结果将指导我们选择先导化合物，以验证这种方法在疾病相关的动物模型中的细胞功能和能力。最终，这些研究代表了开发新型口服治疗以改善2型糖尿病患者血糖控制的重要早期步骤，具有独特的改变疾病进展的潜力。