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REGENERATION OF PANCREATIC BETA CELLS

胰腺β细胞的再生

基本信息

批准号：
6786878
负责人：
GLADYS N. TEITELMAN
金额：
$ 6.89万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
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

项目摘要

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(摘自申请者摘要)：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。新生，B细胞从非B细胞分化而来，可能对新生儿和成人的胰岛细胞重新繁殖很重要老鼠。PI具有胚胎胰岛的表型特征祖细胞，并试图阐明是否出现类似的细胞在成年人身上。研究结果表明，在发育过程中，胰升糖素(A)、胰岛素(B)、生长抑素(Delta)胰多肽 (PP)细胞由多潜能干细胞产生。它们的共同点是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)。以确定成人胰腺是否含有B干细胞的成年小鼠胰腺组织对链脲佐菌素(SZ)所致糖尿病患者进行检测。SZ-处理诱导 PDX-1+前体细胞诱导的胰岛分化胰岛素(IN)合成。成人新生B细胞的数量小鼠的血糖水平很低，动物的血糖水平仍然很高。《少年派》测试了正常血糖对健康有益的假说胰岛细胞再生和初步实验显示了惊人的 SZ处理的成年小鼠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 SZ或是否也发生在I型糖尿病模型中的作用，即NOD 老鼠。它还将决定胰岛素的初始效果是否- 诱导正常血糖是对B细胞分化的促进。最后，将确定持续的正常血糖是否促进新分化的胰岛素细胞的存活以及这些细胞细胞能够维持正常的血糖水平解读治疗性胰岛素治疗。这些研究提高了相当数量的B细胞将发生改造的可能性在糖尿病小鼠中，通过外源性给予IN来实现正常血糖。也许持续的高血糖将促进他们的生存和成熟。完全分化的B细胞有可能足以维持葡萄糖的动态平衡。这些结果产生了对B细胞的恢复和实现 I型糖尿病患者血糖正常。