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Interrogating the ubiquitin pathway to understand and treat cytokine-induced beta-cell death in type 1 diabetes

探究泛素通路以了解和治疗 1 型糖尿病中细胞因子诱导的 β 细胞死亡

基本信息

批准号：
10278303
负责人：
ROHIT N. KULKARNI
金额：
$ 55.68万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10278303
关键词：
Alberta province Apoptosis Area Autoimmune Diabetes Autoimmune Diseases Beta Cell Binding Biology Cell Death Cell Line Cell Survival Cell physiology Cellular biology Chemicals Clinical Complex Complications of Diabetes Mellitus Cytokine Signaling Development Diabetes Mellitus Diabetic mouse Disease Equilibrium Event Gene Expression Profiling Genetic Goals Heart Human Hypoglycemia Immune Immune Targeting In Vitro Individual Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Interferon Type II Interleukin-1 beta JAK2 gene Kidney Label Lead Lysine Measurable Measurement Mediating Methods Modeling Morbidity - disease rate Mus Mutate Non obese Outcome Pancreas Pathway interactions Patients Peripheral Nerves Phenotype Phosphorylation Phosphotransferases Post-Translational Protein Processing Process Proteins Proteomics Retina Risk Role STAT1 gene Signal Transduction Structure of beta Cell of islet TNF gene Therapeutic Tyrosine Ubiquitin Ubiquitination Universities activity-based protein profiling analog cellular targeting chemoproteomics cytokine early detection biomarkers improved in vivo innovation islet kinase inhibitor knock-down mortality risk mouse model novel therapeutic intervention preservation prevent response screening small molecule tool

项目摘要

PROJECT SUMMARY The loss of insulin-producing beta cells in the pancreas results in an absolute requirement for injected insulin, causing significant risks of mortality from hypoglycemia and morbidity from diabetic complications in peripheral nerves, the retina, the heart, and the kidney. A key goal of efforts to treat T1D is to stop this cellular attack, either by halting the immune mis-recognition of beta cells or by protecting beta cells from cell death. However, a critical barrier to progress in the field is a lack of complete understanding of the cellular events in the islet that contribute to the loss of beta-cell mass. Using a phenotypic screening approach, we discovered BRD0476, a compound that is selectively active against cytokine-mediated apoptosis. Further study of this compound revealed that it binds the deubiquitinase USP9X to halt JAK2 and STAT1 signaling in response to IFNγ. We determined that JAK2 can be rendered signaling incompetent by ubiquitination, and that by modulating USP9X, we can tip the balance toward reduced JAK2 kinase activity, even in the presence of IFNγ. These results point to an emerging role for ubiquitination in regulating beta-cell apoptosis in T1D, and suggest that a greater understanding of this process (and its potential dysregulation) in the early stages of T1D development could lead to 1) the ability to identify at-risk individuals, and 2) novel therapeutic strategies to preserve beta-cell mass in early-stage T1D. Using our probe BRD0476 and chemical biology tools not previously applied to islet biology, we will improve our understanding of the role of USP9X in beta-cell survival in vitro and in vivo through the following aims: In Aim 1, we will characterize the mode of JAK2 inhibition by USP9X in human islets. In Aim 2, we will assess effects of inhibiting USP9X-JAK2 (with BRD0476) on development and progression of autoimmune diabetes in a mouse model of type 1 diabetes. In Aim 3, we will profile deubiquitinase (DUB) expression and activity in human islets during early T1D development, using activity-based protein profiling (ABPP) and global ubiquitome measurements. The successful outcomes of this proposal are 1) a greater understanding of mechanisms to promote beta-cell survival in early T1D, and 2) a chemical probe to provide translational proof-of-concept. This project will set the stage for developing a biomarker of early-stage T1D development, as well as advanced therapeutic strategies for preventing beta-cell apoptosis in early-stage T1D, representing a potentially curative approach.

项目总结