Using ex vivo, in vivo models and patient mutations to interrogate pancreatic exocrine-endocrine cross talk
Using ex vivo, in vivo models and patient mutations to interrogate pancreatic exocrine-endocrine cross talk
批准号:
10706558
负责人:
Saumya Das
金额:
$91.95万
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
项目状态:
未结题
起止时间:
2022-09-20 至 2026-06-30
关键词:
2&apos-DeoxythymidineAcinar CellAdultAnatomyAutophagocytosisBeta CellBiological ModelsBiologyCardiovascular DiseasesCause of DeathCell CommunicationCell LineCell physiologyCell secretionCellsCellular StressCellular biologyCessation of lifeCoculture TechniquesCommunicationCommunitiesComplementDataData SetDefectDevelopmentDiabetes MellitusDiseaseDisease ProgressionDuct (organ) structureDuctal Epithelial CellEmbryonic DevelopmentEndocrineEstersExhibitsExocrine pancreasExtracellular SpaceFunctional disorderGene MutationGenesGenetically Engineered MouseGoalsGrowthHip region structureHormonesHumanIncubatedInsulin-Dependent Diabetes MellitusIslet CellKidney FailureLabelLipaseMalignant NeoplasmsMalignant neoplasm of pancreasMetabolicModelingMolecularMorbidity - disease rateMutationOrganoidsOutcomeOutputPancreasPancreatic DiseasesPancreatitisPathogenesisPathway interactionsPatientsPhysiologyProcessPropertyReagentResearchResolutionResourcesRoleSecondary toSliceSmall RNATestingTherapeuticTissuesTransfer RNATransplantationVariantblood glucose regulationcell typecombatdiabetes riskendoplasmic reticulum stressexosomeexperimental studyextracellular vesiclesgene producthuman diseasehumanized mousein vitro Modelin vivoin vivo Modelinduced pluripotent stem cellinsightinsulin secretionintercellular communicationisletlipid disordermutantnon-diabeticnovelparacrinerisk variantsenescencestress granuletransmission processuptake
中文摘要
项目摘要
1型糖尿病及其代谢后果仍然是最重要的生物医学问题之一。
在美国和世界范围内的挑战。除了与糖尿病特别相关的发病率外,
与并发症如肾衰竭、脂质紊乱、心血管疾病和癌症有关,
是全球死亡的主要原因。因此,迫切需要更好地了解其发病机制
促进胰岛素分泌β细胞的损失,以计划更好的治疗方法来对抗这种疾病。几
研究认为,构成胰腺小生境的不同细胞类型有助于胰腺炎的发病机制。
疾病的过程。因此,更好地理解主要细胞之间的细胞间通信,
因为腺泡和导管细胞以及胰岛细胞是必需的。我们研究了突变羧基酯的作用
脂肪酶(CEL)基因,在腺泡细胞中表达,对它被β细胞摄取的能力,并导致其缺陷,
功能和成长。这项提议的目的是发现当腺泡分泌蛋白质组在细胞内表达时,
与人胰岛和β细胞一起孵育。这些研究的数据将产生新的
假设的测试,这将允许更深入地询问人类腺泡,导管和
胰岛细胞我们将在本提案中解决以下目标:目标1)确定人类腺泡的能力,
与人类导管细胞相比,直接影响胰岛细胞功能。我们将从人类中分离和表征EV,
诱导多能干细胞(hIPS)来源的腺泡与导管谱系定向类器官,并孵育
它们与人胰岛/β细胞和人胰腺切片一起直接检查对胰岛细胞的影响,
生物学我们还将检查EV货物,特别关注来自转移RNA的片段。
目的2)我们将询问EV的能力,EV来源于从hiPS产生的腺泡衍生的类器官
来自MODY 8患者的细胞,以直接调节人胰岛β细胞生物学。人类类器官的使用,
人胰腺切片将提供我们研究的翻译相关性。获得的结果和数据集
这些实验将补充人类胰岛研究网络的努力,并提供新的
与广大科学界共享资源。
英文摘要
PROJECT SUMMARY
Type 1 diabetes and its metabolic consequences continue to be among the most significant biomedical
challenges in the US and worldwide today. In addition to morbidities specifically related to diabetes the disease
is associated with complications such as renal failure, lipid disorders, cardiovascular disease and cancer and is
a major cause of death worldwide. Thus there is an urgent need for a better understanding of the pathogenesis
that promotes the loss of insulin-secreting beta cells to plan better therapeutics to combat the disease. Several
studies have argued that diverse cell types that make up the pancreatic niche contribute to the pathogenesis of
the disease process. Thus a better understanding of the inter-cellular communication between major cells such
as the acinar and duct cells and islet cells are warranted. We have studied the role of the mutant carboxy ester
lipase (CEL) gene, expressed in acinar cells, on its ability to be taken up by beta cells and cause defects in its
function and growth. The goal of this proposal is to discover the changes that occur when secretome from acinar
versus duct cells are incubated with human islet and β-cells. The data from these studies will generate new
hypothesis for testing that will allow a deeper interrogation of the cross-talk between human acinar, duct and
islet cells. We will address the following Aims in this proposal: Aim 1) Determine the ability of human acinar
versus human duct cells to directly impact islet cell function. We will isolate and characterize EVs, from human
induced pluripotent stem (hIPS) cell derived acinar- versus duct-lineage committed organoids, and incubate
them with human islet/β-cells and human pancreas slices to directly examine the consequences on islet cell
biology. We will also examine the EV cargo with a particular focus on fragments derived from transfer RNAs.
Aim 2) We will interrogate the ability of EVs, derived from acinar-derived organoids generated from the hiPS
cells from MODY8 patients, to directly regulate human islet-β-cell biology. The use of human organoids and
human pancreas slices will provide translational relevance of our studies. The results and datasets obtained
from these experiments will complement the efforts of the Human Islet Research Network and provide novel
resources to be shared with the larger scientific community.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Characterization of beta-cell-specific extracellular vesicle cargo as functional biomarkers for type I DM disease
-
批准号:10517890
-
项目类别:
-
资助金额:$82.0万
-
财政年份:2022
-
负责人:Saumya Das
-
依托单位:
Using ex vivo, in vivo models and patient mutations to interrogate pancreatic exocrine-endocrine cross talk
-
批准号:10594228
-
项目类别:
-
资助金额:$95.84万
-
财政年份:2022
-
负责人:Saumya Das
-
依托单位:
Characterization of beta-cell-specific extracellular vesicle cargo as functional biomarkers for type I DM disease
-
批准号:10706576
-
项目类别:
-
资助金额:$75.37万
-
财政年份:2022
-
负责人:Saumya Das
-
依托单位:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
-
批准号:9894484
-
项目类别:
-
资助金额:$96.07万
-
财政年份:2020
-
负责人:Saumya Das
-
依托单位:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
-
批准号:10417068
-
项目类别:
-
资助金额:$97.7万
-
财政年份:2020
-
负责人:Saumya Das
-
依托单位:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
-
批准号:10176560
-
项目类别:
-
资助金额:$98.54万
-
财政年份:2020
-
负责人:Saumya Das
-
依托单位:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
-
批准号:10630193
-
项目类别:
-
资助金额:$94.93万
-
财政年份:2020
-
负责人:Saumya Das
-
依托单位:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
-
批准号:9811730
-
项目类别:
-
资助金额:$48.37万
-
财政年份:2019
-
负责人:Saumya Das
-
依托单位:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
-
批准号:10350010
-
项目类别:
-
资助金额:$110.01万
-
财政年份:2019
-
负责人:Saumya Das
-
依托单位:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
-
批准号:10018945
-
项目类别:
-
资助金额:$45.49万
-
财政年份:2019
-
负责人:Saumya Das
-
依托单位:
Novel Therapy for Long QT Syndrome
-
批准号:9457493
-
项目类别:
-
资助金额:$59.92万
-
财政年份:2016
-
负责人:Saumya Das
-
依托单位:
Optimization of biofluid ex-RNA isolation and characterization.
-
批准号:8845766
-
项目类别:
-
资助金额:$7.42万
-
财政年份:2013
-
负责人:Saumya Das
-
依托单位:
Multi-group collaborative proposal: Diversity and function of prevalent uncharacterized exRNA species from tissue and biofluid
-
批准号:9452490
-
项目类别:
-
资助金额:$7.78万
-
财政年份:2013
-
负责人:Saumya Das
-
依托单位:
Plasma miRNA predictors of adverse mechanical and electrical remodeling after MI
-
批准号:9324478
-
项目类别:
-
资助金额:$4.33万
-
财政年份:2013
-
负责人:Saumya Das
-
依托单位:
Plasma miRNA predictors of adverse mechanical and electrical remodeling after MI
-
批准号:8581981
-
项目类别:
-
资助金额:$50.0万
-
财政年份:2013
-
负责人:Saumya Das
-
依托单位:
Plasma miRNA predictors of adverse mechanical and electrical remodeling after MI
-
批准号:9128774
-
项目类别:
-
资助金额:$100.0万
-
财政年份:2013
-
负责人:Saumya Das
-
依托单位:
Plasma miRNA predictors of adverse mechanical and electrical remodeling after MI
-
批准号:8710366
-
项目类别:
-
资助金额:$50.0万
-
财政年份:2013
-
负责人:Saumya Das
-
依托单位:
Plasma miRNA predictors of adverse mechanical and electrical remodeling after MI
-
批准号:9059891
-
项目类别:
-
资助金额:$8.7万
-
财政年份:2013
-
负责人:Saumya Das
-
依托单位:
Computational discovery of SGK1 inhibitors for the treatment of heart disease
-
批准号:7976659
-
项目类别:
-
资助金额:$21.73万
-
财政年份:2010
-
负责人:Saumya Das
-
依托单位:
Computational discovery of SGK1 inhibitors for the treatment of heart disease
-
批准号:8091463
-
项目类别:
-
资助金额:$28.94万
-
财政年份:2010
-
负责人:Saumya Das
-
依托单位:
海外基金