Cell Lineage and Homeostasis of Pancreatic Beta Cells in the Aged
Cell Lineage and Homeostasis of Pancreatic Beta Cells in the Aged
批准号:
8868872
负责人:
JAKE ALDEN KUSHNER
金额:
$32.34万
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-09-01 至 2017-05-31
关键词:
AcuteAdolescentAgeBeta CellBiology of AgingCell CycleCell LineageCell ProliferationCell SizeCell divisionCell physiologyCellsCollaborationsDate of birthDevelopmentDevelopmental BiologyDiabetes MellitusDuctalElderlyExhibitsFinancial compensationFunctional disorderGoalsHealthHomeostasisInjuryInsulinKineticsKnowledgeLabelLigationLongevityMammalsMediatingMetabolicMethodsModelingMusNatural regenerationNon-Insulin-Dependent Diabetes MellitusPancreasPancreatectomyPancreatic InjuryPathogenesisPatientsPlayRefractoryResearchRoleStimulusStreptozocinStructure of beta Cell of isletTestingThymidineage relatedagedanalogbasecell growthcellular targetingdiabetes mellitus therapyexenatidehealthy agingimprovedinnovationnovelpathological agingprogenitorpromoterregenerativeresponseresponse to injuryself-renewaltoolyoung adult
中文摘要
描述(由申请人提供):我们的目标是了解胰腺β细胞起源和命运随年龄变化的发育生物学。有限的β细胞再生可能在2型糖尿病(T2 DM)中发挥重要作用,特别是在老年人中。在T2 DM患者中,β细胞质量减少,这可能损害β细胞功能。在过去,ss细胞团被认为是高度动态的。但我们的研究表明,β细胞再生在成熟时受到限制。因此,我们推测,与年龄相关的β细胞再生下降有助于糖尿病的发病机制。虽然自我更新是年轻小鼠中β细胞生长的主要机制,但在某些情况下也可能发生β细胞新生。令人惊讶的是,老年小鼠的β细胞群继续扩大,尽管ss细胞更新率严重降低。因此,我们假设ss细胞新生可能有助于老年人β细胞群的扩增。因此,实现以下目标:1.)确定健康老年小鼠胰腺β细胞的寿命和细胞来源。我们将量化老化β细胞的细胞更新率,并定义健康衰老中新β细胞的起源。2.)病理性衰老中胰腺β细胞的寿命和细胞来源的确定。我们将量化老年小鼠对再生刺激、损伤(部分胰腺切除术、胰腺导管结扎术、链脲佐菌素介导的β细胞损失)或糖尿病治疗(exendin- 4、西格列汀)的β细胞群扩增。然后,我们将定义病理老化中新β细胞的起源细胞,结合再生刺激进行ss细胞的谱系追踪研究。最后,我们将检验β细胞更新的“复制不应期”限制老年β细胞进入细胞周期的假设。我们将确定老年小鼠对再生刺激的反应中β细胞的细胞分裂次数。总之,这些研究使用创新的工具来精确地跟踪衰老的β细胞及其祖细胞在再生过程中的命运。
英文摘要
DESCRIPTION (provided by applicant): Our goal is to understand the developmental biology of pancreatic beta-cell origin and fate as a function of age. Limited beta-cell regeneration may play a fundamental role in type 2 diabetes mellitus (T2DM), especially in the elderly. beta-cell mass is reduced in T2DM patients, which may impair beta-cell function. In the past ss-cell mass was considered to be highly dynamic. But our studies suggest that beta-cell regeneration is restricted in maturity. We therefore hypothesize that the age-related decline in beta-cell regeneration contributes to diabetes pathogenesis. Whereas self-renewal is the primary mechanism of beta-cell growth in young mice, beta-cell neogenesis might also occur under some circumstances. Surprisingly, beta-cell mass continues to expand in aged mice, despite severely reduced ss-cell turnover rates. We therefore hypothesize that ss-cell neogenesis could contribute to beta-cell mass expansion in the elderly. Thus, the following aims: 1.) Determine the lifespan and cell of origin of pancreatic beta cells in healthy aged mice. We will quantify cell turnover rates of aged beta-cells, and define the origin of new beta- cells in healthy aging. 2.) Determine the lifespan and cell of origin of pancreatic beta-cells in pathological aging. We will quantify beta-cell mass expansion of aged mice in response to regenerative stimuli, injury (partial pancreatectomy, pancreatic ductal ligation, streptozotocin mediated beta-cell loss) or diabetes therapies (exendin- 4, sitagliptin). We will then define the cell of origin of new beta-cells in pathological aging, carrying out lineage tracing studies of ss-cells combined with regenerative stimuli. Finally, we will test the hypothesis that the "replication refractory period" of beta-cell turnover limits cell cycle entry of aged beta cells. We will determine the number of cell divisions of beta-cells in aged mice in response to regenerative stimuli. In summary, these studies use innovative tools to precisely follow fate of aged beta-cells and their progenitors during regeneration.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1371/journal.pone.0159276
发表时间:
2016
期刊:
PloS one
影响因子:
3.7
作者:
[Cox AR, Barrandon O, Cai EP, Rios JS, Chavez J, Bonnyman CW, Lam CJ, Yi P, Melton DA, Kushner JA]
通讯作者:
Kushner JA
Editorial: in praise of scientific review officers.
社论:赞扬科学审查官员。
DOI:
10.1210/me.2014-1179
发表时间:
2014
期刊:
Molecular endocrinology (Baltimore, Md.)
影响因子:
--
作者:
[Elahi,Dariush, Mirmira,RaghavendraG, Kushner,JakeA]
通讯作者:
Kushner,JakeA
Cell Lineage and Homeostasis of Pancreatic Beta Cells in the Aged
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批准号:8164359
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项目类别:
-
资助金额:$35.39万
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财政年份:2011
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负责人:JAKE ALDEN KUSHNER
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依托单位:
Cell Lineage and Homeostasis of Pancreatic Beta Cells in the Aged
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批准号:8321469
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项目类别:
-
资助金额:$34.88万
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财政年份:2011
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负责人:JAKE ALDEN KUSHNER
-
依托单位:
Cell Lineage and Homeostasis of Pancreatic Beta Cells in the Aged
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批准号:8529428
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项目类别:
-
资助金额:$32.48万
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财政年份:2011
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负责人:JAKE ALDEN KUSHNER
-
依托单位:
Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth
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批准号:8004775
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项目类别:
-
资助金额:$0.64万
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财政年份:2010
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负责人:JAKE ALDEN KUSHNER
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依托单位:
Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth
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批准号:7678570
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项目类别:
-
资助金额:$32.9万
-
财政年份:2008
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负责人:JAKE ALDEN KUSHNER
-
依托单位:
Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth
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批准号:8109183
-
项目类别:
-
资助金额:$30.68万
-
财政年份:2008
-
负责人:JAKE ALDEN KUSHNER
-
依托单位:
Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth
-
批准号:7885265
-
项目类别:
-
资助金额:$32.57万
-
财政年份:2008
-
负责人:JAKE ALDEN KUSHNER
-
依托单位:
Bone Morphogenic Proteins as Novel Regulators of Beta Cell Growth
-
批准号:8324525
-
项目类别:
-
资助金额:$30.68万
-
财政年份:2008
-
负责人:JAKE ALDEN KUSHNER
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依托单位:
p130 Regulation of Islet Growth
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批准号:7291416
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项目类别:
-
资助金额:$8.25万
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财政年份:2007
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负责人:JAKE ALDEN KUSHNER
-
依托单位:
p130 Regulation of Islet Growth
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批准号:7458160
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项目类别:
-
资助金额:$8.06万
-
财政年份:2007
-
负责人:JAKE ALDEN KUSHNER
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依托单位:
Cyclin D2 Regulation Of Islet Growth
-
批准号:6800067
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项目类别:
-
资助金额:$13.25万
-
财政年份:2004
-
负责人:JAKE ALDEN KUSHNER
-
依托单位:
Cyclin D2 Regulation Of Islet Growth
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批准号:6935251
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项目类别:
-
资助金额:$13.35万
-
财政年份:2004
-
负责人:JAKE ALDEN KUSHNER
-
依托单位:
Cyclin D2 Regulation Of Islet Growth
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批准号:7276665
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项目类别:
-
资助金额:$13.25万
-
财政年份:2004
-
负责人:JAKE ALDEN KUSHNER
-
依托单位:
Cyclin D2 Regulation Of Islet Growth
-
批准号:6861567
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项目类别:
-
资助金额:$10.25万
-
财政年份:2004
-
负责人:JAKE ALDEN KUSHNER
-
依托单位:
Cyclin D2 Regulation Of Islet Growth
-
批准号:7112367
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项目类别:
-
资助金额:$13.25万
-
财政年份:2004
-
负责人:JAKE ALDEN KUSHNER
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依托单位:
Cyclin D2 Regulation Of Islet Growth
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批准号:6599839
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项目类别:
-
资助金额:$2.52万
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财政年份:2003
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负责人:JAKE ALDEN KUSHNER
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依托单位:
海外基金