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The role of senescent beta cells in T1D and T2D

衰老 β 细胞在 T1D 和 T2D 中的作用

基本信息

批准号：
10708994
负责人：
KLAUS H KAESTNER
金额：
$ 72.13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708994
关键词：
ATAC-seq Ablation Age Alleles Animal Model Autoantibodies Autoimmunity B-Lymphocytes Backcrossings Beta Cell Biological Assay CDKN1A gene CDKN2A gene Cell Aging Cell Cycle Cell Cycle Arrest Cell physiology Cells Cellular Stress Characteristics Chronic Cre driver Cytometry DNA DNA Damage Data Development Diabetes Mellitus Disease Excision Functional disorder Gene Expression Profile Genes Genetic Genotoxic Stress Glucose Intolerance Histones Human Human Characteristics Hyperglycemia Image Inbred NOD Mice Inflammatory Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Knowledge Metabolic Metabolism Modality Modeling Molecular Morphology Mus Outcome Oxidative Stress Pancreas Pathology Pathway interactions Pharmaceutical Preparations Phenotype Population Prevalence Property Recovery Reporting Research Role Signal Transduction Stimulus TP53 gene Testing Therapeutic Transgenic Mice Tumor Suppressor Proteins Type 2 diabetic Viral Vector Work Xenograft Model Xenograft procedure acute stress age related blood glucose regulation cell injury cell type clinical practice cohort diabetic diabetic patient epigenomics gain of function genetic signature genomic tools human data improved inhibitor islet islet autoimmunity loss of function methylome mouse model non-diabetic novel prevent programs response senescence sex single-cell RNA sequencing stressor telomere tumorigenesis type I and type II diabetes type I diabetic

项目摘要

U01 Application: The role of senescent beta cells in T1D and T2D Abstract Recent studies including our own suggest a marked increase in β-cells expressing key components of cellular senescence in islets from Type 1 diabetes (T1D) and Type 2 diabetic (T2D) patients, implicating β-cell senescence as a critical contributor to islet dysfunction. Recently, it was reported that ablation of senescent cells by non-specific senolysis in mouse models of T1D and T2D improved diseease outcome. However, these studies did not determine which senescent cell type was relevant to the beneficial effect, nor did they address to what extent senescence occurs in the human endocrine pancreas before and during the development of T1D and T2D. To close this knowledge gap, in Specific Aim 1 we will determine the prevalence, transcription signatures and epigenomic landscapes of β-cell senescence in T1D, pre-T1D and T2D donors using immunostaining, imaging mass cytometry, single cell RNAseq, single cell ATACseq, DNA methylome determination and Cut-and-Tag analysis for key histone marks. In addition, we will evaluate the hypothesis that irreparable damage to telomeres drives senescence in β-cells, a possible scenario that could provide a mechanism for senescence to occur in islet cells of diabetic patients. In Specific Aim 2, we will test whether metabolic and/or inflammatory stressors drive senescence in human β-cells and determine the effect of senescence on β-cell function using scRNAseq and secretome analysis. We will evaluate if induction of senescence and the senescence-associated secretory phenotype (SASP) in human islet cells is p16 dependent, employing the pseudo-islets approach and using our hyperglycemic xeno-transplantation model to assess the direct effect of senolytics on human islet function. In Specific Aim 3, we will employ a novel transgenic mouse, the ‘SenKiller’ model, to enable cell-type specific and inducible ablation of senescent cells in any lineage including β-cells. Using this mouse model in combination with the appropriate β-cell specific Cre driver, we will provide a definitive answer to the question if senescent β-cells are critical in the development of glucose intolerance in models of T2D and islet autoimmunity in models of T1D. Together, this proposal will determine the occurrence of senescence among islet cells from T1D and T2D donors using large cohorts and multiple experimental modalities, explore the natural drivers of senescence and consequences to islet function as well as secretion of pro-inflammatory substances, and employ novel mouse models to unequivocally determine if elimination of senescent b-cells impacts diabetes progression in mouse models of T1D and T2D. The data generated here will address burning questions in the field, namely, is senescence increased in islets from diabetic patients, and are these cells important in the overall pathophysiology of T1D and T2D. These critical questions will have therapeutic relevance regarding the potential efficacy of targeting senescent β-cells with senolytic therapies.

应用：衰老β细胞在T1D和T2D中的作用