Regional and lobular heterogeneity of human pancreas morphology and function in type 1 diabetes pathogenesis
1型糖尿病发病机制中人胰腺形态和功能的区域和小叶异质性
基本信息
- 批准号:10400943
- 负责人:
- 金额:$ 41.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-24 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcinar CellAcinus organ componentAddressAffectAmylasesAreaAtrophicAutoantibodiesAutoimmunityBeta CellBiological AssayBlood VesselsBody Weight decreasedBody mass indexC-PeptideCell CommunicationCell physiologyCellsCellular biologyCessation of lifeCharacteristicsDataDevelopmentDiabetes MellitusDiabetes autoantibodiesDiabetes preventionDigestionDiseaseElementsEndocrineEnvironmentEnzymesEventExocrine pancreasExtracellular MatrixFunctional disorderGene ExpressionGlucagonHeadHealthHeterogeneityHistologicHormonesHumanImmuneIn SituIndividualInfiltrationInflammatory ResponseInsulinInsulin-Dependent Diabetes MellitusInvestigationIslet CellIslets of LangerhansKnowledgeLipaseLobularLobuleLocationMeasuresMechanicsMediatingModificationMolecularMorphologyMusNeuronsOrganOrgan DonorOrgan WeightOutputPancreasPathogenesisPathogenicityPathologicPatternPersonsPhysiologyPositioning AttributePredispositionProceduresProcessRegulationResistanceResourcesRoleSerumSignal TransductionSliceSorting - Cell MovementStimulusStructure of beta Cell of isletTailTechniquesTechnologyTestingThree-dimensional analysisTissue DonorsTissue Slice TechnologyTissuesTrypsinogenTumor-infiltrating immune cellsVariantVascularizationWeightautoimmune pathogenesisblood glucose regulationcellular imagingdensitydiabetes pathogenesisexperienceimaging studyimprovedinsulitisisletlymphatic vesselmorphometrynerve supplynew therapeutic targetnon-diabeticnovelperipheral bloodpreservationpreventprogramsregional differenceresponsesextraittwo-dimensional
项目摘要
Through programs such as the Network for Pancreatic Organ donors with Diabetes (nPOD), highly valuable
tissues from persons with various stages and durations of type 1 diabetes (T1D) are now available. As a result,
our collective knowledge of the pathogenic events underlying T1D development has improved substantially.
However, studies simultaneously assessing functional and morphological traits of the human pancreas have not
been performed, limiting our understanding of the processes governing organ physiology in health versus
pathophysiology in T1D. Despite being in important research resource, investigations of isolated islets are
confounded by the isolation procedure, which induces an inflammatory response, morphological modifications,
and altered gene expression. Furthermore, the isolation procedure relies on the structural integrity of the islets
to withstand the enzymatic and mechanical sorting process. Most importantly, separation of islets from their
surrounding tissue removes any influence and information regarding the local adjacent elements, which could
be of importance, especially in pathological settings. We believe the characterization of islets as well as exocrine
tissues (function, regulation, and cellular interactions) and their roles in the pathogenesis of T1D would be
improved through studies of viable human pancreatic tissue containing intact islets and acini. We propose to
utilize the extremely novel pancreas tissue slice technology to substantially expand our knowledge of endocrine
and exocrine function and their interaction in normal (i.e., control) and T1D pancreas tissues obtained through
the nPOD program. This technology, originally established by Dr. Speier (mPD/PI, HMGU), produces “slices” of
fresh pancreatic tissue with minimal mechanical damage and without enzymatic digestion; enabling in situ
investigations of islet cell biology in a relatively unperturbed tissue setting. Following functional stimulation
assays for endocrine (insulin and glucagon) and exocrine secretion (amylase, lipase, trypsinogen) as well as
dynamic imaging studies of cellular signaling (Ca2+ flux), slices will be fixed and analyzed by 3D morphometry.
Amongst the many questions that will be addressed, we seek to improve our understanding on the functional
implications of the lobular and regional (i.e., head, body or tail) heterogeneous pancreatic morphology, including
islet density, size and cellular composition, exocrine enzyme expression and distribution, as well as vascular and
neuronal density. Furthermore, we aim to address its role in the distinct lobular and regional pathological
progression of T1D (i.e., insulitis, β-cell dysfunction and destruction, loss of acinar cell/organ mass). Thus, we
pose to test the hypothesis that the disparate organ weight loss as well as the lobular heterogeneity of insulitis
and β-cell destruction within the human T1D pancreas is the result of inter-regional and intra-lobular
differences in endocrine and exocrine pancreas morphology and function. Our objective is to correlate islet
and exocrine physiology and pathophysiology to their location within the pancreas and to cellular characteristics
of the surrounding microenvironment; efforts that should impact attempts at T1D prevention/reversal.
通过糖尿病胰腺器官捐赠者网络(NPOD)等项目,非常有价值
来自不同阶段和病程的1型糖尿病(T1D)患者的组织现在可以买到。结果,
我们对T1D发生的致病事件的集体知识有了很大的提高。
然而,同时评估人类胰腺的功能和形态特征的研究还没有
限制了我们对控制健康中器官生理学的过程的理解
T1D的病理生理学。尽管有重要的研究资源,但对孤立岛屿的调查是
被分离程序搞混了,这会引起炎症反应,形态改变,
并改变了基因表达。此外,隔离程序依赖于胰岛的结构完整性
经得起酶和机械分选过程。最重要的是,将小岛与它们的
周围组织去除关于局部相邻元素的任何影响和信息,这可能
很重要,特别是在病态环境中。我们认为胰岛和外分泌的特征
组织(功能、调节和细胞相互作用)及其在T1D发病机制中的作用
通过对含有完整胰岛和腺泡的活的人胰腺组织的研究而得到改进。我们建议
利用极新的胰腺组织切片技术大幅扩展我们对内分泌的认识
和外分泌功能及其在正常(即对照)和T1D胰腺组织中的相互作用
NPOD程序。这项技术最初是由斯皮尔博士(MPD/PI,HMGU)创立的,可以生产出
新鲜的胰腺组织,机械损伤最小,无需酶消化;实现原位
在相对不受干扰的组织环境中进行胰岛细胞生物学的研究。跟随功能刺激
内分泌(胰岛素和高血糖素)和外分泌(淀粉酶、脂肪酶、胰蛋白酶原)以及
细胞信号(钙离子通量)的动态成像研究,切片将被固定并通过三维形态计量学进行分析。
在将要解决的许多问题中,我们试图提高我们对功能
小叶和区域性(即头部、体部或尾部)异质性胰腺形态的含义,包括
胰岛密度、大小和细胞组成、外分泌酶的表达和分布以及血管和
神经元密度。此外,我们的目标是探讨其在不同的小叶和区域病理中的作用。
T1D的进展(即,岛炎、β细胞功能障碍和破坏、腺泡细胞/器官质量丧失)。因此,我们
摆姿势测试不同器官重量减轻以及小叶异质性的胰岛素炎的假设
人T1D胰腺内β细胞的破坏是区域间和小叶内的结果
内分泌和外分泌胰腺形态和功能的差异。我们的目标是关联小岛
以及外分泌生理学和病理生理学对它们在胰腺内的位置和细胞特性的影响
对周围微环境的影响;应对T1D预防/逆转尝试产生影响的努力。
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)
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MARK A. ATKINSON其他文献
MARK A. ATKINSON的其他文献
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{{ truncateString('MARK A. ATKINSON', 18)}}的其他基金
Biorepository and Coordinating Center for Studies on Cardiovascular Complications of Human Type 1 Diabetes
人类1型糖尿病心血管并发症研究生物储存库和协调中心
- 批准号:
10879240 - 财政年份:2022
- 资助金额:
$ 41.44万 - 项目类别:
Biorepository and Coordinating Center for Studies on Cardiovascular Complications of Human Type 1 Diabetes
人类1型糖尿病心血管并发症研究生物储存库和协调中心
- 批准号:
10672443 - 财政年份:2022
- 资助金额:
$ 41.44万 - 项目类别:
Biorepository and Coordinating Center for Studies on Cardiovascular Complications of Human Type 1 Diabetes
人类1型糖尿病心血管并发症研究生物储存库和协调中心
- 批准号:
10512888 - 财政年份:2022
- 资助金额:
$ 41.44万 - 项目类别:
Co-registration of Cell Organization, Phenotype and Function in the Human Pancreas During Type 1 Diabetes
1 型糖尿病期间人类胰腺细胞组织、表型和功能的共同注册
- 批准号:
10343979 - 财政年份:2021
- 资助金额:
$ 41.44万 - 项目类别:
Co-registration of Cell Organization, Phenotype and Function in the Human Pancreas During Type 1 Diabetes
1 型糖尿病期间人类胰腺细胞组织、表型和功能的共同注册
- 批准号:
10673726 - 财政年份:2021
- 资助金额:
$ 41.44万 - 项目类别:
Co-registration of Cell Organization, Phenotype and Function in the Human Pancreas During Type 1 Diabetes
1 型糖尿病期间人类胰腺细胞组织、表型和功能的共同注册
- 批准号:
10490416 - 财政年份:2021
- 资助金额:
$ 41.44万 - 项目类别:
Regional and lobular heterogeneity of human pancreas morphology and function in type 1 diabetes pathogenesis
1型糖尿病发病机制中人胰腺形态和功能的区域和小叶异质性
- 批准号:
10617206 - 财政年份:2020
- 资助金额:
$ 41.44万 - 项目类别:
Regional and lobular heterogeneity of human pancreas morphology and function in type 1 diabetes pathogenesis
1型糖尿病发病机制中人胰腺形态和功能的区域和小叶异质性
- 批准号:
10223289 - 财政年份:2020
- 资助金额:
$ 41.44万 - 项目类别:
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