REGENERATION OF PANCREATIC BETA CELLS

胰腺β细胞的再生

• 批准号: 2906198
• 负责人: GLADYS N. TEITELMAN
• 金额: $ 15.58万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906198
• 关键词: NOD mouse; autoradiography; blood glucose; cell differentiation; cell proliferation; developmental neurobiology; disease /disorder model; electron microscopy; glucagon; gluconeogenesis; glucose metabolism; histogenesis; homeostasis; immunocytochemistry; insulin; insulin dependent diabetes mellitus; mature animal; newborn animals; pancreatic islets; pancreatic polypeptide; somatostatin; streptozotocin; transcription factor

DESCRIPTION (Adapted from applicant's abstract): Pancreatic B cell death leads to profound insulin deficiency, hyperglycemia and type I diabetes. Neogenesis, the differentiation of B cells from non-B cells, could be important to islet cell re-population in neonates and adult mice. The PI has characterized the phenotype of embryonic islet progenitor cells and sought to elucidate whether similar cells appeared in adults. The findings suggest that, during development the glucagon(a), insulin(B), somatostatin (delta) pancreatic polypeptide (PP) cells were produced by multipotential stem cells. Common to these cells is coexpression of the homeodomain protein, PDX-1 (pancreas duodenum homeobox gene-1). To determine whether adult pancreas contained B stem cells, pancreatic tissues of adult mice rendered diabetic by streptozotocin (SZ) were examined. SZ-treatment induced differentiation in islets of PDX-1+ precursor cells that initiated insulin (IN) synthesis. The number of newly formed B cells in adult mice was low and the animals remained severely hyperglycemic. The PI tested the hypothesis that normoglycemia had a beneficial effect on islet cell regeneration and preliminary experiments revealed a striking increase in B cell neogenesis in adult SZ-treated mice rendered normoglycemic by exogenous insulin. The PI will determine whether B cell neogenesis is due to a specific effect of SZ or if it also occurs in Type I diabetes models i.e. the NOD mouse. It will also determine whether the initial effect of insulin- induced normoglycemia is the enhancement of B cell differentiation. Finally, it will be determined whether sustained normoglycemia promotes the survival of the newly differentiated insulin cells and whether these cells are able to maintain normal blood glucose levels following interpretation of the therapeutic insulin treatment. These studies raise the possibility that a significant number of B cells will reform in diabetic mice rendered euglycemic by exogenously administered IN. Perhaps sustained homoglycemia will promote their survival an maturation. It is possible that fully differentiated B-cells will suffice to maintain glucose homeostasis. These results have implications for the restoration of B cells and the achievement of normoglycemia in type I diabetic patients.

描述（改编自申请人摘要）：胰腺B细胞 死亡会导致严重的胰岛素缺乏、高血糖和I型糖尿病。 糖尿病新生，B细胞从非B细胞分化， 可能对新生儿和成人胰岛细胞再增殖有重要意义 小鼠 PI表征了胚胎胰岛的表型 并试图阐明是否出现了类似的细胞 在成年人中。 研究结果表明，在发育过程中， 胰高血糖素（a）、胰岛素（B）、生长抑素（δ）胰多肽 (PP)细胞由多潜能干细胞产生。 常见于这些 细胞共表达同源结构域蛋白PDX-1（胰腺 十二指肠同源盒基因-1）。 为了确定成年胰腺 含有B干细胞，成年小鼠的胰腺组织 糖尿病患者行链脲佐菌素（SZ）检查。 SZ处理诱导 PDX-1+前体细胞的胰岛中的分化， 胰岛素（IN）合成。 成人新生B细胞数 小鼠的血糖水平较低，并且动物保持严重的高血糖。 的PI 检验了诺莫司汀对 胰岛细胞再生和初步实验显示， SZ处理的成年小鼠中B细胞新生增加 正常血糖的外源性胰岛素。 PI将确定B细胞新生是否是由于特定的 SZ的作用，或者如果它也发生在I型糖尿病模型中，即NOD 老鼠. 它还将确定胰岛素的初始效果- 诱导的正常增殖是B细胞分化的增强。 最后，将确定持续的正常血糖是否会促进 新分化的胰岛素细胞的存活以及这些细胞是否 细胞能够维持正常的血糖水平， 解释治疗性胰岛素治疗。 这些研究 增加了大量B细胞改革的可能性 在通过外源性给予IN而使血糖正常的糖尿病小鼠中。 也许持续的高血糖会促进他们的生存， 成熟 完全分化的B细胞有可能 足以维持葡萄糖稳态。 这些结果 对恢复B细胞和实现 在I型糖尿病患者中，