Capacity and Mechanisms of Beta Cell Regeneration in Humans

描述（由申请人提供）：1型和2型糖尿病都是由胰岛素分泌不足引起的，在这两种疾病中，这在很大程度上可归因于产生胰岛素的胰腺β细胞的损失。这两种疾病都可以通过胰腺移植替代胰腺细胞来治愈，但这需要长期的免疫抑制，而且器官捐赠者比糖尿病患者少得多。另一种恢复胰腺β细胞的方法是促进患者体内β细胞的再生。这合理吗？在啮齿类动物中是可以的，但人类的细胞生物学与啮齿类动物明显不同。本申请中提出的研究将解决这个问题，在多大程度上β细胞再生在人类中是可行的？这一目标将通过解决四个具体目标来实现。首先，我们将确定人类童年时期β细胞质量增加的程度（以及通过何种机制）。其次，我们将确定β细胞质量在人类肥胖反应中增加的程度（以及通过何种机制）。第三，我们将确定β细胞质量是否在非糖尿病老年人中维持，如果是，通过什么机制维持。第四，我们研究了脐带血干细胞在人体内转分化为β细胞的能力（因为这种方法已经在临床试验中）。

DESCRIPTION (provided by applicant): Both type 1 and 2 diabetes are caused by inadequate insulin secretion, and in both diseases this can be ascribed in large part to loss of pancreatic beta cells that produce insulin. Both diseases can be cured by replacement of pancreatic beta cells by pancreas transplantation but this requires life long immunosuppression and there are far fewer organ donors than people with diabetes. An alternative approach to restoring pancreatic beta cells is to foster regeneration of beta cells in the patient. Is this plausible? In rodents yes, but human beta cell biology is clearly different to that in rodents. The studies proposed in this application would address the question, to what extent is beta cell regeneration feasible in humans? This goal will be approached by addressing four Specific Aims. First, we will establish the extent (and by what mechanisms) beta cell mass increases in human childhood. Second, we will establish the extent (and by what mechanisms) beta cell mass increases in response to obesity in humans. Third, we will establish if beta cell mass is maintained in non diabetic aging humans, and if so by what mechanisms. Fourth, we examine the ability of cord blood stem cells to transdifferentiate into beta cells in humans (since this approach is already in clinical trials). To accomplish these goals we will obtain well preserved human pancreas at autopsy in patients in who a recent ambulatory general medical examination (and labs) is available. We will apply a recently developed model to compute beta cell turnover permitting us to quantify beta cell turnover, and distinguish between new beta cell formation from beta cell replication and replication independent sources. These studies would be undertaken by a consortium with a long established track record of productive research with these resources.