REGENERATION OF PANCREATIC BETA CELLS

胰腺β细胞的再生

• 批准号: 6177608
• 负责人: GLADYS N. TEITELMAN
• 金额: $ 16.04万
• 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 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177608
• 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（改编自申请人的摘要）：胰腺 B 细胞 死亡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 细胞与非 B 细胞的分化， 对新生儿和成人的胰岛细胞重新增殖可能很重要 老鼠。 PI 表征了胚胎胰岛的表型 祖细胞并试图阐明是否出现了类似的细胞 在成人中。 研究结果表明，在开发过程中 胰高血糖素(a)、胰岛素(B)、生长抑素(δ)胰多肽 (PP)细胞是由多能干细胞产生的。 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)。 判断是否有成人胰腺 含有 B 干细胞，成年小鼠的胰腺组织 糖尿病患者可通过链脲佐菌素（SZ）进行检查。 SZ治疗诱导 PDX-1+ 前体细胞的胰岛分化开始 胰岛素（IN）的合成。 成人新形成的B细胞数量 小鼠血糖水平较低，而动物仍然处于严重高血糖状态。 PI 检验了血糖正常对健康有益的假设 胰岛细胞再生和初步实验揭示了惊人的 成年 SZ 治疗小鼠 B 细胞新生增加 通过外源性胰岛素使血糖正常。 PI 将确定 B 细胞新生是否是由于特定的原因所致。 SZ 的影响或者它是否也发生在 I 型糖尿病模型（即 NOD）中 老鼠。 它还将确定胰岛素的初始效果是否 诱导正常血糖是B细胞分化的增强。 最后，将确定持续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 治疗性胰岛素治疗的解释。 这些研究 增加大量 B 细胞发生重组的可能性 在糖尿病小鼠中，通过外源性给予IN使血糖正常。 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。 这些结果有 对 B 细胞的恢复和实现的影响 I型糖尿病患者血糖正常。