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
- 来源:
- 关键词:ATAC-seqAblationAddressAgeAllelesAnimal ModelAutoimmunityB-LymphocytesBackBeta CellBiological AssayCDKN1A geneCDKN2A geneCell AgingCell CycleCell Cycle ArrestCell physiologyCellsCellular StressCharacteristicsChronicCre driverCytometryDNADNA DamageDataDevelopmentDiabetes MellitusExcisionFunctional disorderGene Expression ProfileGenesGeneticGenotoxic StressGlucose IntoleranceHistonesHumanHuman CharacteristicsHyperglycemiaImageInbred NOD MiceInflammatoryInsulinInsulin-Dependent Diabetes MellitusIslet CellIslets of LangerhansKnowledgeMetabolicMetabolismModalityModelingMolecularMorphologyMusNon-Insulin-Dependent Diabetes MellitusOutcomeOxidative StressPancreasPathologyPathway interactionsPharmaceutical PreparationsPhenotypePopulationPrevalencePropertyRecoveryReportingResearchRoleStimulusSumTP53 geneTestingTherapeuticTransgenic MiceTumor Suppressor ProteinsType 2 diabeticViral VectorWorkXenograft procedureacute stressage relatedblood glucose regulationcell injurycell typeclinical practicecohortdiabeticdiabetic patientepigenomicsgenetic signaturegenomic toolshuman dataimprovedinhibitorinsulin dependent diabetes mellitus onsetisletislet autoimmunityloss of functionmethylomemouse modelnon-diabeticnovelpreventprogramsresponsesenescencesexsingle-cell RNA sequencingstressortelomeretransplant modeltumorigenesistype I and type II diabetestype 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.
U01应用:衰老的β细胞在T1D和T2D中的作用
摘要
最近的研究包括我们自己的研究表明,表达细胞关键成分的β细胞显著增加
1型糖尿病(T1D)和2型糖尿病(T2D)患者胰岛衰老,与β细胞有关
衰老是胰岛功能障碍的关键因素。最近,有报道称,消融治疗衰老
在T1D和T2D小鼠模型中,通过非特异性感受器分解的细胞改善了疾病的结局。然而,这些
研究没有确定哪种衰老细胞类型与有益效果有关,也没有解决
人内分泌胰腺在发育前和发育过程中的衰老程度如何
T1D和T2D。为了弥合这一知识鸿沟,在具体目标1中,我们将确定流行率、转录
T1D、Pre-T1D和T2D供者β细胞衰老的特征和表观基因组图谱
免疫染色、图像质量分析、单细胞RNAseq、单细胞ATACseq、DNA甲基组
关键组蛋白标记的测定和切割标签分析。此外,我们还将评估假设
端粒不可修复的损伤会导致β细胞衰老,这一可能的情况可能会提供
糖尿病患者胰岛细胞衰老的机制。在具体目标2中,我们将测试
代谢和/或炎症应激致人β细胞衰老,并决定
用单链RNA序列和分泌组分析衰老对β细胞功能的影响。我们将评估是否会诱导
人胰岛细胞衰老及衰老相关分泌表型(SASP)为p16
依赖,使用假性胰岛方法和使用我们的高血糖异种移植模型
评估感觉神经降解剂对人类胰岛功能的直接影响。在具体目标3中,我们将使用一部小说
转基因小鼠,‘SenKiller’模型,使细胞类型特异性和可诱导的衰老细胞在
任何血统,包括β细胞。将此小鼠模型与适当的β细胞特异性Cre结合使用
驱动程序,我们将提供一个明确的答案,如果衰老的β细胞在发展中的关键
T2D模型的糖耐量异常和T1D模型的胰岛自身免疫。总而言之,这项提议将
用大样本队列研究T1D和T2D供者胰岛细胞衰老的发生
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,并利用新的小鼠模型明确地
确定消除衰老的b细胞是否影响T1D和T2D小鼠模型的糖尿病进展。
这里产生的数据将解决现场的紧迫问题,即小岛衰老是否加剧
这些细胞在T1D和T2D的整体病理生理学中是否重要。这些
有关靶向衰老β细胞的潜在疗效的关键问题将具有治疗相关性
用感冒药治疗。
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
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)
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
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
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
Collaborative Research: CDS&E: An experimentally validated, interactive, data-enabled scientific computing platform for cardiac tissue ablation characterization and monitoring
合作研究:CDS
- 批准号:
2245152 - 财政年份:2023
- 资助金额:
$ 75.85万 - 项目类别:
Standard Grant