PHENOTYPIC CHANGES IN CULTURED PANCREATIC EXOCRINE CELLS

本申请的总体长期目标是更好地 了解胰管和腺泡细胞的谱系关系 以及这些细胞在成年后改变其表型的潜力 动物 正常成人胰腺是一种有丝分裂活性低的组织 由腺泡、导管和胰岛细胞排列组成， 表型稳定。 胰腺的两大疾病， 胰腺炎和癌症，涉及细胞分裂和 外分泌细胞表型 急性胰腺炎后细胞分裂 恢复正常功能。 当组织 恢复的腺泡细胞可以表现出改变的形态， 去分化或导管细胞样。 最后，差异化的 形态学回归。 在胰腺癌中， 发生分裂和异常细胞生长。 因为大多数的癌症 胰腺具有未分化的（导管细胞样）形态，它们具有 被认为是导管起源，但他们的可能性， 应考虑由表型改变的腺泡细胞引起。 一 更好地理解诱导和维持的调节 分化，以及胰腺癌细胞表型变化的可能性。 外分泌细胞将增加知识，这将是有用的理解， 这些胰腺疾病的病因和可能的治疗。 具体目标是：（1）记录和确定 腺泡细胞表型转换为导管样细胞， 原代培养的腺泡样细胞;（2）确定表型 培养中导管细胞稳定性及其作为免疫原的适用性 产生针对导管细胞和导管细胞前体的mAb;（3）开发 区分成熟导管和腺泡的单克隆抗体 细胞及其前体细胞;（4）使用单克隆抗体， 为了跟踪这些细胞类型特异性标志物的出现和丢失， 胰腺在胚胎中发育;（5）跟踪导管的表达 使用胎儿发育在体内生长腺泡细胞上的细胞标志物， 从实验诱导的急性胰腺炎恢复作为模型。

The overall, long-term objective of this application is to better understand the lineage relationships of pancreatic duct and acinar cells and the potential for these cells to alter their phenotypes in the adult animal. The normal adult pancreas is a tissue of low mitotic activity composed of an arrangement of acinar, duct, and islet cells whose phenotypes are stable. The two major diseases of the pancreas, pancreatitis and cancer, involve cell division and alterations in exocrine cell phenotype. After acute pancreatitis cell division is activated for recovery of normal function. While the tissue is recovering acinar cells can exhibit an altered morphology and may appear dedifferentiated or duct cell-like. Eventually, the differentiated morphology returns. In pancreatic cancer loss of regulation of cell division and aberrant cell growth occurs. Because most cancers of the pancreas have an undifferentiated (duct cell-like) morphology, they have been considered to be of ductal origin, but the possibility that they arise from acinar cells of altered phenotype should be considered. A better understanding of regulation of the induction and maintenance of differentiation, and the potential for phenotypic changes in pancreatic exocrine cells will add knowledge that will be useful understanding the etiology and possible treatments of these pancreatic diseases. The specific aims are: (1) to document and determine the extent of the phenotypic switching of acinar cells to duct-like cells and back to acinar-like cells in primary culture; (2) to determine the phenotypic stability of duct cells in culture and their suitability as immunogen for generating mAbs to duct cells and duct cell precursors; (3) to develop monoclonal antibodies that differentiate between mature duct and acinar cells and their precursor cell(s); (4) using the monoclonal antibodies, to follow the appearance and loss of these cell-type specific markers as the pancreas develops in the embryo; (5) to follow the expression of duct cell markers on growing acinar cells in vivo using fetal development and recovery from experimentally-induced acute pancreatitis as models.