Survival and potential of insulin-deficient beta cells in type 1 diabetes
1 型糖尿病中胰岛素缺乏的 β 细胞的存活率和潜力
基本信息
- 批准号:10583924
- 负责人:
- 金额:$ 72.7万
- 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:2022-09-20 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AgonistAutoantibodiesAutoimmunityAutomobile DrivingBeta CellBiological AssayBiological ModelsBiological ProductsBlood VesselsCell physiologyCellsCellular Metabolic ProcessCharacteristicsChromogranin ACytometryDNADNA MethylationDataDetectionDiabetes MellitusDiseaseDown-RegulationEndocrineEndoplasmic ReticulumExtravasationFunctional disorderGCG geneGene ExpressionGenetic TranscriptionGenetically Engineered MouseGlycoproteinsHormonesHumanHyperglycemiaImageImmuneImmune systemImmunofluorescence ImmunologicImmunologicsIn SituIn VitroInflammationInflammatoryInsulinInsulin-Dependent Diabetes MellitusInterferonsIslet CellIslets of LangerhansLesionLobularLongevityLymphaticMapsMetabolicMetabolic PathwayMethodsMethylationModalityModelingMolecularMusNatural HistoryNon-Insulin-Dependent Diabetes MellitusOrgan DonorPancreasPathway interactionsPatientsPeriodicityPhenotypePilot ProjectsPlayProcessProductionProinsulinProteinsQuality of lifeResidenciesRoleSTAT5B geneSamplingSignal PathwaySignal TransductionSliceStainsSystemTamoxifenTestingTherapeuticTissuesWFS1 geneautoimmune pathogenesisbasecytokinedrug candidateeffective interventionendoplasmic reticulum stressexperimental studyimmunoreactivityimprovedin vivoinhibitorinsightinsulin dependent diabetes mellitus onsetinsulin secretionisletlaser capture microdissectionmethylation patternmimeticsmouse modelmutantmutant mouse modelnew technologynon-diabeticnovelrepositoryresponsesenescencetargeted treatmenttherapeutic candidatetherapeutic developmenttherapeutic evaluationtherapeutic targettraffickingtranscriptome sequencing
项目摘要
SUMMARY / ABSTRACT
Recent evidence put forth by our group and others suggests that the pancreas of patients with recent-onset type
1 diabetes (T1D) contains a significant number of “empty” beta cells that have lost the ability to secrete mature
insulin but retained other hallmark features such as proinsulin expression. The mechanisms that underlie
formation of such cells and their fate remain poorly understood. We hypothesize that empty beta cells, which
are invisible to standard insulin immunostaining and potentially also to the immune system, play important roles
in the pathophysiology of T1D while holding therapeutic potential for reversion of diabetes. We propose in depth
experiments to characterize empty beta cells, using MACSima ultra high-content immunofluorescence imaging
to assess in situ expression of 78 immune and pancreas cell markers, including vascular and lymphatic
annotation with signatures of inflammation, extravasation/trafficking, and immune cell residency in autoantibody
positive (AAb+) and T1D donors as compared to donors with type 2 diabetes (T2D) and non-diabetic controls
available through the Network for Pancreatic Organ donors with Diabetes (nPOD) repository. We will compare
insulin containing versus insulin negative islets, within and across donors, to identify empty beta cells and
determine how they correlate with islet, acinar, and immune cell phenotypes. These data will serve as a template
for a serial section to undergo laser capture microdissection (LCM) of insulin containing islets, insulin negative
islets, and acinar tissue regions, which will be subjected to bulk RNAseq as well as our novel method for
quantifying beta cells based on DNA methylation patterns. In addition, we will use a novel mouse model (beta
cell-specific, tamoxifen-inducible Adar1-mutant) and cultured human pancreas slices to functionally interrogate
molecular pathways underlying the formation of empty beta cells. Specifically, we propose to leverage these two
model systems to test therapeutic candidates— including an incretin mimetic (GLP1), an endoplasmic reticulum
(ER) stress inhibitor (ISRIB), and multiple biologics targeting specific immune subsets— for their ability to
modulate empty beta cells, their insulin content and insulin secretion. We will then correlate these functional data
with molecular and cellular features of hormone negative islet cells via MACSima, RNAseq, and DNA
methylation. These studies are expected to yield insights into a fundamental yet little understood process taking
place in human T1D. We anticipate that empty beta cells can be re-functionalized, paving the way for therapeutic
development to restore endogenous beta cell function in T1D. Ultimately, when combined with effective
interventions to constrain autoimmunity, it is our hope that the metabolic modalities explored here could provide
a means to reduce insulin requirements or even achieve insulin independence after T1D onset, dramatically
improving longevity and quality of life for these patients.
总结/摘要
我们小组和其他人提出的最新证据表明,新近发病型患者的胰腺
1型糖尿病(T1 D)含有大量的“空”β细胞,这些细胞已经失去了分泌成熟β细胞的能力。
胰岛素,但保留其他标志性特征,如胰岛素原表达。背后的机制
这些细胞的形成和它们的命运仍然知之甚少。我们假设,空β细胞,
对标准胰岛素免疫染色不可见,也可能对免疫系统不可见,
在T1 D的病理生理学中,同时具有逆转糖尿病的治疗潜力。我们建议在深度
使用MACSima超高含量免疫荧光成像表征空β细胞的实验
评估78种免疫和胰腺细胞标志物的原位表达,包括血管和淋巴
自身抗体中炎症、外渗/运输和免疫细胞驻留特征的注释
阳性(AAb+)和T1 D供体与2型糖尿病(T2 D)供体和非糖尿病对照相比
糖尿病胰腺器官捐赠者网络(NPOD)。我们将比较
在供体内和供体之间,含有胰岛素的胰岛与胰岛素阴性胰岛,以鉴定空β细胞,
确定它们如何与胰岛、腺泡和免疫细胞表型相关。这些数据将作为模板
对于连续切片,对含有胰岛素的胰岛、胰岛素阴性的胰岛进行激光捕获显微切割(LCM
胰岛和腺泡组织区域,其将经受批量RNAseq以及我们的用于
基于DNA甲基化模式定量β细胞。此外,我们将使用一种新的小鼠模型(beta
细胞特异性的,他莫昔芬诱导的Adar 1突变体)和培养的人胰腺切片进行功能性询问,
空β细胞形成的分子途径。具体来说,我们建议利用这两个
用于测试治疗候选物的模型系统-包括肠促胰岛素模拟物(GLP 1)、内质网
(ER)应激抑制剂(ISRIB)和多种靶向特定免疫亚群的生物制剂-因为它们能够
调节空β细胞、其胰岛素含量和胰岛素分泌。然后我们将这些功能数据
通过MACSima、RNAseq和DNA分析激素阴性胰岛细胞的分子和细胞特征
甲基化这些研究有望深入了解一个基本但鲜为人知的过程,
在人类T1 D中。我们预计,空β细胞可以重新功能化,为治疗铺平道路。
开发以恢复T1 D中的内源性β细胞功能。最终,当与有效的
干预措施,以限制自身免疫,这是我们的希望,代谢模式探讨这里可以提供
一种在T1 D发作后显著降低胰岛素需求甚至实现胰岛素非依赖性的方法,
提高这些患者的寿命和生活质量。
项目成果
期刊论文数量(0)
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DESMOND Arthur SCHATZ其他文献
DESMOND Arthur SCHATZ的其他文献
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{{ truncateString('DESMOND Arthur SCHATZ', 18)}}的其他基金
Survival and potential of insulin-deficient beta cells in type 1 diabetes
1 型糖尿病中胰岛素缺乏的 β 细胞的存活率和潜力
- 批准号:
10705841 - 财政年份:2022
- 资助金额:
$ 72.7万 - 项目类别:
Non-Invasive Diagnosis of Human Beta Cell Damage and Death
人类β细胞损伤和死亡的无创诊断
- 批准号:
8813900 - 财政年份:2014
- 资助金额:
$ 72.7万 - 项目类别:
TrialNet: University of Florida Clinical Center and Network
TrialNet:佛罗里达大学临床中心和网络
- 批准号:
8776517 - 财政年份:2009
- 资助金额:
$ 72.7万 - 项目类别:
TrialNet: University of Florida Clinical Center and Network
TrialNet:佛罗里达大学临床中心和网络
- 批准号:
8468690 - 财政年份:2009
- 资助金额:
$ 72.7万 - 项目类别:
TrialNet: University of Florida Clinical Center and Network
TrialNet:佛罗里达大学临床中心和网络
- 批准号:
7785653 - 财政年份:2009
- 资助金额:
$ 72.7万 - 项目类别:
TrialNet: University of Florida Clinical Center and Network
TrialNet:佛罗里达大学临床中心和网络
- 批准号:
8073484 - 财政年份:2009
- 资助金额:
$ 72.7万 - 项目类别:
TrialNet: University of Florida Clinical Center and Network
TrialNet:佛罗里达大学临床中心和网络
- 批准号:
7938968 - 财政年份:2009
- 资助金额:
$ 72.7万 - 项目类别:
TrialNet: University of Florida Clinical Center and Network
TrialNet:佛罗里达大学临床中心和网络
- 批准号:
8831775 - 财政年份:2009
- 资助金额:
$ 72.7万 - 项目类别:
TrialNet: University of Florida Clinical Center and Network
TrialNet:佛罗里达大学临床中心和网络
- 批准号:
8288867 - 财政年份:2009
- 资助金额:
$ 72.7万 - 项目类别:
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