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Project 1 - Immunologic and Cellular Mechanisms of T1D Modifier Mutations

项目 1 - T1D 修饰突变的免疫学和细胞机制

基本信息

批准号：
10642553
负责人：
Lucienne CHATENOUD
金额：
$ 26.17万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-13 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642553
关键词：
Acceleration Activities of Daily Living Adoptive Transfer Affect Agreement Antigen Presentation Attention Autoantigens Beta Cell Bone Marrow Transplantation Breeding CRISPR/Cas technology Cell Count Cells Cellular Immunology Chromogranin A Collaborations DNA Sequence Alteration Data Development Diabetes Mellitus Disease Ethylnitrosourea Event FOXP3 gene Gene Targeting Genes Genetic Genome Goals Health Hematopoietic stem cells Human Immune Immune system Immunologics Inbred NOD Mice Incidence Induced Mutation Infiltration Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knockout Mice Laboratories Maps Measurement Mediating Metabolic Missense Mutation Molecular Mus Mutagens Mutation Organoids Orthologous Gene Pathogenesis Pathogenicity Pathologic Patients Peptides Phenotype Phosphoric Monoester Hydrolases Predisposition Process Proteins Regulatory T-Lymphocyte Research T cell therapy T-Cell Receptor T-Lymphocyte Techniques Technology Testing Therapeutic Intervention Time Tissues Transgenic Organisms Work cell type conditional knockout diabetogenic dominant genetic mutation experimental study improved in vivo innovation insulin sensitivity insulitis islet lymphoid organ molecular sequence database neonate new therapeutic target novel prevent success synergism tool transcriptome

项目摘要

PROJECT SUMMARY/ABSTRACT The goal of Project 1 is to understand in detail the pathological consequences of ENU-induced mutations implicated by Core B and Core C to modify the T1D phenotype of NOD/NckH mice, and to determine the cellular mechanisms by which those mutations impact the development of T1D. As we have done for Dusp10, a spontaneous mutation bred to homozygosity in our lab based on phenotypic selection, we will analyze each selected mutation to determine which salient immunopathological steps—recognized as hallmarks of T1D initiation and/or progression—are affected. To that end, we will use tools such as analysis of pancreatic islet infiltration (i.e. insulitis); measurement of the numbers and the in vivo functional capacity in various lymphoid organs of diabetogenic or regulatory CD4+FoxP3+ T lymphocytes; and analysis of islet antigen presentation using adoptive transfer of diabetogenic cells expressing the transgenic BDC2.5 T cell receptor (specific for an autoantigenic fusion peptide incorporating insulin and chromogranin A sequences) into 4-week-old recipients. We will pay particular attention to mechanisms of insulin resistance, and to the definition of markers of increased β-cell sensitivity witnessed with particular genetic mutations. In doing so it is plausible that novel immunopathological steps will be discovered. Second, we will investigate the contribution of particular tissues or cell types bearing each mutation to the development of T1D using bone marrow transplantation, adoptive transfer in neonates, islet transplantation, tissue-specific conditional knockout mice, and islet organoid cultures in the presence or absence of immune cells. Results will provide important guidance to Project 2, focused on molecular pathogenesis. We will perform cellular mechanistic studies to understand of the effects of mutations in Paqr8 (protective), and Dusp10, Rapgef1, and Xpnpep1 (exacerbating), identified in our initial collaboration. We expect to actively pursue mechanistic studies of four to six proteins at a time, adding one new protein per year by mutual agreement with Project 2. We expect that strong synergy between Projects will accelerate our progress. An important question we will address is the relevance of our findings to human health. To understand how mutations identified in NOD mice relate to human T1D, we will study the effects of selected mutations in NOD mice bearing a T1D-susceptible humanized immune system modified to contain or lack the orthologous mutations in human hematopoietic stem cells and/or human islet cells. We will also identify human T1D patients with mutations in genes orthologous to those we implicated in our screen of NOD mice. Our findings will uncover new therapeutic targets for treatment of T1D and help to improve prediction of T1D onset in humans.

项目总结/文摘