IRE1 alpha inhibitors for type 2 diabetes

IRE1 α 抑制剂治疗 2 型糖尿病

基本信息

批准号：
9044234
负责人：
Bradley J Backes
金额：
$ 19.96万
依托单位：
OPTIKIRA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044234
关键词：
Address Adipose tissue Adult Affect American Aniline Apoptosis Apoptotic Attenuated Beta Cell Biological Availability Cell Death Cell Line Cell model Cell physiology Cells Cessation of life Chemicals Chronic Clinical Development Diabetes Mellitus Diagnosis Disease Disease Progression Endoplasmic Reticulum Engineering Exhibits Fatty acid glycerol esters Fibroblasts Functional disorder Goals Healthcare Hepatocyte Hyperactive behavior Hyperglycemia Hypothalamic structure In Vitro Individual Insulin Insulin Receptor Insulin Resistance Integral Membrane Protein Intervention Islets of Langerhans Liver Longevity MAPK8 gene Mediating Messenger RNA Modeling Molecular Chaperones Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity OmpR protein Oral Output Pancreas Pathway interactions Patients Peripheral Permeability Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Positioning Attribute Prevention Proteins Public Health RNA Splicing Receptor Signaling Relative (related person)Ribonucleases Risk Series Signal Pathway Signal Transduction Solubility Testing Tunicamycin Tyrosine Urea analog animal tissue cost design diabetic endoplasmic reticulum stress feeding glycemic control improved in vivo inhibitor/antagonist insulin receptor substrate 1 protein insulin secretion insulin signaling kinase inhibitor mRNA Transcript Degradation member mouse model mutant novel prevent protein folding public health relevance research study response sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): The American Diabetes Association has declared type 2 diabetes (T2D) a public health crisis. T2D begins as a state of compensated insulin resistance; frank disease develops when ~50% of insulin-producing pancreatic islet β-cells of affected individuals undergo cell death. Endoplasmic reticulum (ER) stress has emerged as a central underlying mechanism that drives the progression from obesity to T2D. In the periphery, obesity-induced ER stress can impair proper insulin signaling. In pancreatic islets, glucotoxicity and lipotoxicity-induced ER stress contributes to β-cell dysfunction and apoptosis. We have identified IRE1α as the master unfolded protein response regulator that determines cell fate under ER stress, and have demonstrated that IRE1α inhibitors we call KIRAs (Kinase Inhibitor RNase Attenuators) block ER stress-driven β-cell dysfunction and apoptosis in vivo. We believe that KIRAs will also act to reduce peripheral insulin resistance and propose proof-of-concept experiments addressing insulin signaling in the liver. We will demonstrate that KIRAs can correct faulty insulin signaling in ER stress-challenged liver cells and optimize their profile to support subsequent development in T2D. We believe a drug intervention that addresses both peripheral insulin resistance and pancreatic β-cell dysfunction and apoptosis has great disease-modifying potential. The specific aims of the proposal are: 1: Demonstrate that KIRAs can correct insulin signaling in a cellular model of insulin resistance; and, 2: Optimize KIRAs to impart a profile that supports development in T2D.

描述（由申请人提供）：美国糖尿病协会已宣布 2 型糖尿病 (T2D) 是一种公共健康危机，T2D 是一种代偿性胰岛素抵抗状态；当约 50% 的产生胰岛素的胰岛 β 细胞出现明显疾病时。受影响的个体经历细胞死亡，内质网应激已成为驱动从肥胖进展为 T2D 的核心潜在机制。内质网应激会损害胰岛中的正常胰岛素信号传导，糖毒性和脂毒性诱导的内质网应激会导致 β 细胞功能障碍和细胞凋亡。我们已确定 IRE1α 是决定内质网应激下细胞命运的主要未折叠蛋白反应调节因子。我们认为，我们称之为 KIRA（激酶抑制剂 RNase 衰减剂）的 IRE1α 抑制剂可在体内阻断 ER 应激驱动的 β 细胞功能障碍和细胞凋亡。 KIRA 还将发挥作用，减少外周胰岛素抵抗，并提出解决肝脏胰岛素信号传导的概念验证实验，我们将证明 KIRA 可以纠正内质网应激挑战的肝细胞中错误的胰岛素信号传导，并优化其特征，以支持后续的发展。我们相信，解决外周胰岛素抵抗和胰腺 β 细胞功能障碍和细胞凋亡的药物干预具有巨大的疾病缓解潜力，该提案的具体目标是： 1：证明 KIRA 可以纠正胰岛素信号传导。胰岛素抵抗的细胞模型；2：优化 KIRA 以提供支持 T2D 发展的概况。