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:
    10583684
  • 负责人:
  • 金额:
    $ 75.85万
  • 依托单位:
  • 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

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.
U01应用:衰老β细胞在T1D和T2D中的作用 摘要 包括我们自己的研究在内的最近的研究表明,表达细胞内关键成分的β细胞显著增加, 1型糖尿病(T1D)和2型糖尿病(T2D)患者胰岛中的衰老,涉及β细胞 衰老是胰岛功能障碍的关键因素。最近,有报道称, 在T1D和T2D小鼠模型中,通过非特异性衰老细胞溶解改善了疾病结果。但这些 研究没有确定哪种衰老细胞类型与有益效果相关,也没有说明 衰老在人类内分泌胰腺发育之前和期间发生的程度 T1D和T2D。为了缩小这一知识差距,在具体目标1中,我们将确定患病率,转录 T1D、前T1D和T2D供体中β细胞衰老的特征和表观基因组景观, 免疫染色、成像质谱细胞术、单细胞RNAseq、单细胞ATACseq、DNA甲基化组 关键组蛋白标记的确定和切割-标记分析。此外,我们将评估假设, 端粒不可修复的损伤驱动β细胞的衰老,这一可能的情况可以提供一种新的方法, 糖尿病患者胰岛细胞发生衰老的机制。在第二阶段,我们将测试 代谢和/或炎性应激物驱动人β细胞的衰老,并决定代谢和/或炎性应激物的作用。 使用scRNAseq和分泌组分析来研究衰老对β细胞功能的影响。我们将评估是否诱导 人胰岛细胞中的衰老和衰老相关分泌表型(SASP)是p16 依赖,采用假胰岛方法,并使用我们的高血糖异种移植模型, 评估senolytics对人类胰岛功能的直接影响。在第三部中,我们将采用一种新的 转基因小鼠,'SenKiller'模型,使细胞类型特异性和诱导性消融衰老细胞, 任何谱系,包括β细胞。使用该小鼠模型与适当的β细胞特异性Cre 驱动程序,我们将提供一个明确的答案,如果衰老的β细胞是至关重要的发展, T2D模型中的葡萄糖耐受不良和T1D模型中的胰岛自身免疫。总之,这一提议将 使用大型队列确定来自T1D和T2D供体的胰岛细胞中衰老的发生, 多种实验模式,探索衰老的自然驱动因素和对胰岛功能的影响 以及促炎物质的分泌,并采用新的小鼠模型, 在T1D和T2D小鼠模型中确定衰老B细胞的消除是否影响糖尿病进展。 这里产生的数据将解决该领域的紧迫问题,即胰岛衰老是否增加 这些细胞在T1D和T2D的总体病理生理学中是重要的。这些 关于靶向衰老β细胞的潜在功效的关键问题将具有治疗相关性 进行衰老清除疗法

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

KLAUS H KAESTNER其他文献

KLAUS H KAESTNER的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('KLAUS H KAESTNER', 18)}}的其他基金

The role of senescent beta cells in T1D and T2D
衰老 β 细胞在 T1D 和 T2D 中的作用
  • 批准号:
    10708994
  • 财政年份:
    2022
  • 资助金额:
    $ 75.85万
  • 项目类别:
Innovative Genetic Approaches to Enhance Liver Repopulation and Reduce Cancer Risk and Progression
增强肝脏再生并降低癌症风险和进展的创新遗传学方法
  • 批准号:
    10434813
  • 财政年份:
    2020
  • 资助金额:
    $ 75.85万
  • 项目类别:
Innovative Genetic Approaches to Enhance Liver Repopulation and Reduce Cancer Risk and Progression
增强肝脏再生并降低癌症风险和进展的创新遗传学方法
  • 批准号:
    10217062
  • 财政年份:
    2020
  • 资助金额:
    $ 75.85万
  • 项目类别:
Innovative Genetic Approaches to Enhance Liver Repopulation and Reduce Cancer Risk and Progression
增强肝脏再生并降低癌症风险和进展的创新遗传学方法
  • 批准号:
    10654627
  • 财政年份:
    2020
  • 资助金额:
    $ 75.85万
  • 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
  • 批准号:
    10252957
  • 财政年份:
    2019
  • 资助金额:
    $ 75.85万
  • 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
  • 批准号:
    10020973
  • 财政年份:
    2019
  • 资助金额:
    $ 75.85万
  • 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
  • 批准号:
    10675236
  • 财政年份:
    2019
  • 资助金额:
    $ 75.85万
  • 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
  • 批准号:
    10568985
  • 财政年份:
    2019
  • 资助金额:
    $ 75.85万
  • 项目类别:
The Human Pancreas Analysis Program for Type 2 Diabetes
2 型糖尿病人类胰腺分析项目
  • 批准号:
    10261669
  • 财政年份:
    2019
  • 资助金额:
    $ 75.85万
  • 项目类别:
Regulatory cascades in gastrointestinal proliferation
胃肠道增殖的调节级联反应
  • 批准号:
    9474868
  • 财政年份:
    2017
  • 资助金额:
    $ 75.85万
  • 项目类别:

相似海外基金

Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
  • 批准号:
    24K21101
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
  • 批准号:
    24K11201
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
  • 批准号:
    24K11281
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
  • 批准号:
    2338890
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334777
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334775
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Continuing Grant
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
  • 批准号:
    EP/Z001145/1
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Fellowship
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334776
  • 财政年份:
    2024
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Continuing Grant
Cryo laser-ablation system (157+193nm) with 'triple-quad' plasma mass spectrometer, Cryo-LA-ICPMS/MS
带有“三重四极杆”等离子体质谱仪、Cryo-LA-ICPMS/MS 的冷冻激光烧蚀系统 (157 193nm)
  • 批准号:
    515081333
  • 财政年份:
    2023
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Major Research Instrumentation
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
  • 批准号:
    2320040
  • 财政年份:
    2023
  • 资助金额:
    $ 75.85万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了