Capacity and Mechanisms of Beta Cell Regeneration in Humans

描述(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，这在很大程度上可以归因于产生胰岛素的胰岛β细胞的丧失。这两种疾病都可以通过胰腺移植替换胰腺β细胞来治愈，但这需要终生的免疫抑制，而且器官捐赠者比糖尿病患者要少得多。另一种恢复胰岛β细胞的方法是促进患者体内的胰岛细胞再生。这听起来可信吗？在啮齿动物中，是的，但人类β细胞生物学显然不同于啮齿动物。这项申请中提出的研究将解决这样一个问题，即人类β细胞再生在多大程度上是可行的？这一目标将通过实现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(以及增加的机制)。其次，我们将确定人类因肥胖而导致的β细胞质量增加的程度(以及增加的机制)。第三，我们将确定在非糖尿病衰老的人类中，β细胞质量是否保持不变，如果是，是通过什么机制。第四，我们检查了脐带血干细胞在人类体内转分化为β细胞的能力(因为这种方法已经在临床试验中)。 为了实现这些目标，我们将在尸检患者中获得保存良好的人胰腺，这些患者最近进行了动态全身医学检查(和实验室)。我们将应用最近开发的一个模型来计算β细胞周转，使我们能够量化贝塔细胞周转，并区分来自贝塔细胞复制和复制独立来源的新的贝塔细胞形成。这些研究将由一个财团进行，该财团在利用这些资源进行生产性研究方面有着长期的记录。

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.