Creating b-cells to cure type 1 diabetes

他们的目标是通过鉴定祖细胞和正常发育所需的分子来创造分泌胰岛素的B细胞，以恢复1型糖尿病患者的B细胞功能。小鼠和人类多能胚胎干细胞、胎鼠胰腺和成人胰腺导管细胞将被用作祖细胞B细胞的来源。比较研究将提供关于人类B细胞个体发育的更完整的图景。为胚胎干细胞-类胚体(EB)-EB来源细胞、胎儿胰腺和成人胰腺导管细胞开发的培养系统将被用于筛选和鉴定新的生长分化因子，并优化体外产生B细胞或(重新)在体内产生B细胞的参数。允许荧光标记基因和生长转录因子受调控表达的基因构建体将被引入培养细胞或转基因小鼠，以使祖细胞B细胞能够被跟踪和分离。祖细胞B细胞将在基因和蛋白质水平上用已知的新标记分子面板进行分型，产生B细胞的组织的基因表达谱将随着时间的推移进行分析，以揭示更多的候选标记。在小鼠系统中有效的分子和方法将应用于人类ES细胞来源的细胞或胰管细胞。将祖细胞或胰岛素分泌细胞移植到小鼠模型的睾丸、肾被膜下或胰腺中以改善糖尿病的能力将代表概念验证。来自人类ERS细胞或胰管细胞的功能性B细胞，或在体内再生B细胞的生长因子，与适当的免疫治疗一起，可以恢复1型糖尿病患者的B细胞功能。

They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid bodies (EB) - EB-derived cells, fetal pancreas and adult pancreas duct cells, will be employed to screen for and identify novel growth-differentiation factors and to optimise parameters for creating B cells in vitro or (re) generating B cells in vivo. Genetic constructs allowing regulated expression of fluorescently-tagged marker genes and growth-transcription factors will be introduced into cultured cells or transgenic mice to enable progenitor B cells to be tracked and isolated. Progenitor B cells will be typed with panels of known novel markers molecules at the gene and protein level, and gene expression profiles of tissue yielding B cells will be analysed across time to reveal further candidate markers. Molecules and methods effective in mouse systems will be applied to human ES cell-derived or pancreatic duct cells. The capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when transplanted into the testis, under the kidney capsule or into the pancreas of mouse models would represent proof-of-concept. Functional B cells derived from human ERS cells or pancreas duct cells, or growth factors that regenerate B cells in vivo, could together with appropriate immunotherapy restore B-cell function in people with type 1 diabetes.