Cell Lineage and Homeostasis of Pancreatic Beta Cells in the Aged

描述(由申请者提供)：我们的目标是了解胰腺β细胞起源和命运的发育生物学作为年龄的函数。有限的β细胞再生可能在2型糖尿病(T2 DM)中起基本作用，尤其是在老年人中。T2 DM患者的β细胞质量减少，这可能会损害β细胞的功能。在过去，SS细胞质量被认为是高度动态的。但我们的研究表明，β细胞的再生在成熟期受到限制。因此，我们假设与年龄相关的β细胞再生减少与糖尿病的发病机制有关。虽然自我更新是幼鼠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，尽管ss细胞周转率严重下降，但老年小鼠的β细胞质量仍在继续扩大。因此，我们假设SS细胞的新生可能有助于老年人中的β细胞群的扩张。因此，目标如下：1.)测定健康老年小鼠胰岛β细胞的寿命和来源细胞。我们将量化衰老的β细胞的细胞周转率，并确定健康衰老中新的β细胞的来源。2.)确定病理性衰老过程中胰岛β细胞的寿命和细胞来源。我们将量化老年小鼠在再生刺激、损伤(部分胰腺切除、胰管结扎、链脲佐菌素介导的β细胞丢失)或糖尿病治疗(Exendin-4、Sitagliptin)下的β细胞扩增。然后，我们将确定病理性衰老中新的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，我们将测试假设，即“复制不应期”的贝塔细胞周转限制细胞周期进入老化的贝塔细胞。我们将确定老年小鼠的β细胞对再生刺激的反应细胞分裂数。总而言之，这些研究使用创新的工具来精确跟踪老化的β细胞及其前体细胞在再生过程中的命运。

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.