Cell Lineage and Homeostasis of Pancreatic Beta Cells in the Aged

老年人胰腺β细胞的细胞谱系和稳态

• 批准号: 8164359
• 负责人: JAKE ALDEN KUSHNER
• 金额: $ 35.39万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164359
• 关键词: Acute; Adolescent; Age; Beta Cell; Biology of Aging; Cell Cycle; Cell Lineage; Cell Proliferation; Cell Size; Cell division; Cell physiology; Cells; Collaborations; Date of birth; Development; Developmental Biology; Diabetes Mellitus; Ductal; Elderly; Exhibits; Financial compensation; Functional disorder; Goals; Health; Homeostasis; Injury; Insulin; Kinetics; Knowledge; Label; Ligation; Longevity; Mammals; Mediating; Metabolic; Methods; Modeling; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pancreatectomy; Pancreatic Injury; Pathogenesis; Patients; Play; Refractory; Research; Role; Stimulus; Streptozocin; Structure of beta Cell of islet; Testing; Thymidine; age related; aged; analog; base; cell growth; cellular targeting; diabetes mellitus therapy; exenatide; healthy aging; improved; innovation; novel; pathological aging; progenitor; promoter; regenerative; response; response to injury; self-renewal; tool; young adult

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.

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，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.）的情况。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。