GASTRIC MUCOSAL INJURY AND AGING

许多研究记录了胃粘膜在以下情况下迅速恢复 轻至中度损伤，但对细胞内损伤知之甚少 负责愈合的机制，或者粘膜再生是否 受衰老的影响。根据我们的初步数据，我们假设 (A)衰老与再生能力减弱有关，以及 (B)这可能部分是由于酪氨酸的活性降低 酪氨酸激酶(Tyr-k)和酪氨酸特异性磷酸化水平的降低 调节蛋白，特别是表皮生长因子受体 具有Tyr-k活性的(EGF-R)，以及(C)这导致减少 转录调控基因，导致(D)细胞减少 增殖和上皮再生。 我们现在建议使用高渗盐水诱导的体内损伤模型。 在Fischer-344大鼠中确定(1)是否与年龄有关 粘膜再生的差异可能是由于粘膜的改变 增殖活性、细胞增殖和迁移，以及(2)是否 细胞增殖的差异是年龄相关变化的结果 在黏膜细胞损失率上，以及(3)细胞是否发生变化 增殖/细胞迁移与组织学重建有关 此外，我们还将评估酪氨酸的作用。 激酶，特别是170 kDa磷酸酪氨酸膜蛋白(它 我们已初步确定为EGF-R)在胃的调节中 再生过程中粘膜细胞的增殖。最后，(5)我们将 确定粘膜再生中与年龄相关的变化是否低于 编码截短EGF-R的原癌基因c-erbB-1的调控 含有细胞质激活域的。 从这些研究中获得的信息有可能扩大我们的 对胃粘膜再生过程的认识 确定可能负责维护的一些机制 粘膜完整性。

Many studies have documented rapid recovery of the gastric mucosa following minor to moderate injury, yet little is known about the intracellular mechanisms responsible for healing, or whether mucosal regeneration is affected by aging. On the basis of our preliminary data we hypothesize that (a) aging is associated with diminished regenerative capacity, and that (b) this may in part be due to decreased activation of tyrosine kinases (Tyr-k) and a reduction in tyrosine-specific phosphorylation of regulatory proteins, specifically the epidermal growth factor receptor (EGF-R), which possesses Tyr-k activity, and (c) this results in decreased transcription of regulatory genes, leading to (d) diminished cell proliferation and epithelial regeneration. We now propose using the in vivo model of hypertonic saline-induced injury in the Fischer-344 rats to determine (1) whether the age-related differences in mucosal regeneration could be due to alterations in mucosal proliferative activity, cell proliferation and migration, and (2) whether the differences in cell proliferation are the result of age-related changes in the rate of mucosal cell loss, and (3) whether the changes in cell proliferation/cell migration correlate with histologic restitution of the mucosa; (4) furthermore, we will also evaluate the role of tyrosine kinases, specifically the 170 kDa phosphotyrosine membrane protein (which we have tentatively identified as EGF-R) in the regulation of gastric mucosal cell proliferation during regeneration. Finally, (5) we will determine whether the age-related changes in mucosal regeneration are under the control of the proto-oncogene c-erbB-1 which encodes a truncated EGF-R containing the cytoplasmic kinase domain. The information derived from these studies has the potential to expand our understanding of regenerative processes of the gastric mucosa and to identify some of the mechanisms that may be responsible for maintaining mucosal integrity.