Capacity and Mechanisms of Beta Cell Regeneration in Humans

人类β细胞再生的能力和机制

• 批准号: 7547390
• 负责人: Peter Cawood Butler
• 金额: $ 30.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547390
• 关键词: 5 year old; Address; Adult; Age; Aging; Apoptosis; Autopsy; Beta Cell; Cells; Cellular biology; Childhood; Clinical Trials; Data; Diabetes Mellitus; Disease; Fostering; Funding; Gender; Glucose; Goals; Histocompatibility Testing; Human; Immunosuppression; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Life; Maintenance; Measurement; Modeling; Natural regeneration; Obesity; Operative Surgical Procedures; Organ Donor; Pancreas; Pancreas Transplantation; Patients; Reporting; Research; Resources; Rodent; Source; Stem cell transplant; Stem cells; Structure of beta Cell of islet; Therapy Clinical Trials; Time; Transplant Recipients; Umbilical Cord Blood; United States National Institutes of Health; aged; cell growth; infancy; insulin secretion; medical examination; non-diabetic; response; therapeutic target; tissue regeneration; type I and type II diabetes

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.

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β细胞来治愈，但这需要终身免疫抑制，而且器官捐赠者比糖尿病患者少得多。恢复胰腺β细胞的另一种方法是促进患者β细胞的再生。这是否合理？在啮齿动物中是的，但人类β细胞生物学与啮齿动物明显不同。本申请中提出的研究将解决这样一个问题，即β细胞再生在人类中的可行程度如何？这一目标将通过四个具体目标来实现。首先，我们将确定人类童年时期β细胞数量增加的程度（以及通过何种机制）。其次，我们将确定β细胞数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细胞群是否在非糖尿病老年人中维持，如果是，是通过什么机制维持的。第四，我们研究了脐带血干细胞转分化为人类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，我们将在尸检中获得保存良好的人类胰腺，这些患者最近进行了门诊一般医学检查（和实验室）。我们将应用最近开发的模型来计算β细胞周转率，从而使我们能够量化β细胞周转率，并区分来自β细胞复制的新β细胞形成和复制独立来源。这些研究将由一个在利用这些资源进行富有成效的研究方面有着长期记录的财团进行。