Developing UPR inhibitory KIRAs into oral antidiabetic beta cell-sparing drugs

将 UPR 抑制性 KIRA 开发为口服抗糖尿病 β 细胞保留药物

基本信息

批准号：
10382330
负责人：
Bradley J Backes
金额：
$ 50.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382330
关键词：
Animals Antidiabetic Drugs Apoptosis Beta Cell Biological Availability Cell Differentiation process Cessation of life Characteristics Chemicals Clinic Clinical Clinical Trials Development Diabetes Mellitus Disease Progression Dose Drug Kinetics Endoplasmic Reticulum Endoribonucleases Event Foundations Future Genetic Transcription Goals Grant Homo Human Hyperactivity Hyperglycemia Immune Targeting Immune mediated destruction Immune system Inbred NOD Mice Inflammation Injections Insulin Insulin-Dependent Diabetes Mellitus Integral Membrane Protein Islets of Langerhans Islets of Langerhans Transplantation Laboratories Letters Messenger RNA Modeling Molecular Chaperones Non obese Onset of illness Oral Outcome Output Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase I Clinical Trials Phosphotransferases Production Proinsulin Protein Secretion Proteins Pyrimidine RNA Splicing Reagent Research Research Personnel Ribonucleases Safety Series Signal Pathway Signal Transduction Structure Structure of beta Cell of islet Suicide Testing Validation Work XBP1 gene autoimmune pathogenesis autoreactivity base biological adaptation to stress chronic autoimmune disease clinical candidate design diabetic dimer early onset efficacy study endoplasmic reticulum stress glycemic control humanized mouse insulin dependent diabetes mellitus onset islet lead optimization novel novel therapeutic intervention novel therapeutics pharmacokinetics and pharmacodynamics pharmacophore pre-clinical premature preservation prevent programs protein folding pyridine response response biomarker safety study scaffold small molecule small molecule inhibitor transcription factor transplant model

项目摘要

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of pancreatic beta cells. Recent work from our laboratories has shown that hyperactivation of the unfolded protein response (UPR) to ER stress in the immune-targeted beta cells may be a critical early event in the development of T1D. We have developed novel pharmacological reagents that allow us to manipulate components of the UPR. Importantly, these small molecules delivered to NOD mice can efficaciously prevent and even reverse diabetes in this T1D model. Thus, in this collaborative grant we will capitalize on the complementary expertise of the investigators to optimize these lead molecules for oral delivery, conduct proof of concept studies, and perform key enabling steps needed to advance these candidates into the clinic for treating human patients with T1D.

1 型糖尿病 (T1D) 是一种慢性自身免疫性疾病，其特征是由于免疫介导的胰腺 β 细胞进行性破坏而导致高血糖。我们实验室最近的研究表明，免疫靶向 β 细胞中未折叠蛋白对 ER 应激的过度激活反应 (UPR) 可能是 T1D 发展的关键早期事件。我们开发了新型药理学试剂，使我们能够操纵 UPR 的成分。重要的是，这些小分子输送到 NOD 小鼠体内可以有效预防甚至逆转 T1D 模型中的糖尿病。因此，在这项合作资助中，我们将利用研究人员的互补专业知识来优化这些口服给药的先导分子，进行概念验证研究，并执行将这些候选药物推进临床治疗人类 T1D 患者所需的关键支持步骤。