The Aging Gut:Regulation of Cell Proliferation

超出所提供的空间。 虽然在Fischer-344大鼠中，衰老与胃肠道（GI）粘膜增殖活性增加和细胞凋亡减少有关，但对其调控机制知之甚少。表皮生长因子受体（EGFR）可能在调节这些过程中发挥关键作用。我们最近的数据表明，衰老改变了胃肠道粘膜对EGFR配体，特别是EGF和TGF-α的敏感性，使得低剂量刺激粘膜增殖，而高剂量抑制老年大鼠的这一过程。因此，我们推测粘膜增殖和凋亡的年龄相关变化可能部分是由于粘膜对EGFR配体，特别是TGF-α的敏感性增加，其存在于整个胃肠道中。GI粘膜中EGFR活化的年龄相关性升高也可能部分是内源性EGFR调节因子减少或丢失的结果。这些调节因子的一个潜在的例子可能是ERRP（EGFR相关蛋白），我们最近克隆的一种蛋白质，与大鼠EGFR的外部结构域具有85%的同源性。ERRP在老年大鼠胃肠道粘膜和结肠癌细胞中的表达明显减少。此外，ERRP在结肠癌细胞（HCT-116和Caco-2）中的过表达显著抑制增殖和EGFR活化，但刺激凋亡。我们假设ERRP是EGFR的负调节因子，通过减弱EGFR活化来调节增殖和凋亡。由于ERRP具有EGFR的配体结合结构域，我们进一步假设ERRP与EGFR竞争配体和/或可能与EGFR形成无活性的异源二聚体，导致EGFR活化的抑制。现在提出的我们工作的主要目的是：（A）通过检查（i）TGF-α与胃和结肠粘膜EGFR的结合性质，（ii）胃和/或结肠粘膜增殖和凋亡中的年龄相关差异是否和在多大程度上受EGFR调节，和（iii）内源性TGF-α在调节胃和/或结肠粘膜EGFR酪氨酸激酶和进而增殖和凋亡中的意义，以及（B）确定ERRP在调节EGFR和进而调节衰老期间胃和结肠粘膜增殖和凋亡中的作用，来确定TGF-α和EGFR在调节衰老期间胃和结肠粘膜增殖和凋亡中的作用。这将通过产生ERRP融合蛋白并研究ERRP对年龄增长过程中胃和结肠粘膜中EGFR活化、增殖和凋亡的影响来实现。EFORMANCE SITE（S）（organization，city，state）研究服务John D. Dingell VA Medical Center 4646 JohnR Detroit，MI 48201关键人员==

EXCEED THE SPACE PROVIDED. Although in Fischer-344 rats aging is associated with increased gastrointestinal (GI) mucosal proliferative activity and decreased apoptosis, the regulatory mechanisms are poorly understood. The EGF-receptor (EGFR) likely plays a key role in regulating these processes. Our recent data suggest that aging alters sensitivity of the GI mucosa to EGFR ligands, specifically EGF and TGF-a, such that low doses stimulate mucosal proliferation whereas high doses inhibit this process in aged rats. Thus, we hypothesize that the age-related changes in mucosal proliferation and apoptosis may, in part, be due to increased mucosal sensitivity to EGFR ligands, specifically TGF-a, which is present throughout the GI tract. The age-related rise in EGFR activation in the GI mucosa may also partly be the result of reduction or loss of endogenous EGFR regulatory factor(s). A potential example of these regulatory factors may be ERRP (EGFR Related Protein), a protein we have recently cloned that has 85% homology to the external domain of the rat EGFR. ERRP expression is markedly decreased in the GI mucosa of aged rats and colon cancer cells. Furthermore, overexpression of ERRP in colon cancer cells (HCT-116 and Caco-2) markedly inhibits proliferation and EGFR activation, but stimulates apoptosis. We hypothesize that ERRP is a negative regulator of EGFR that modulates proliferation and apoptosis by attenuating EGFR activation. Since ERRP possesses the ligand binding domain of the EGFR we further hypothesize that ERRP competes with EGFR for ligands and/or may form inactive heterodimers with EGFR resulting in inhibition of EGFR activation. The primary objectives of our work now proposed are:(A) To determine the role of TGF-a and EGFR in regulating gastric and colonic mucosal proliferation and apoptosis during aging by examining (i) binding properties of TGF-a to gastric and colonic mucosal EGFR, (ii) whether and to what extent age-related differences in gastric and/or colonic mucosal proliferation and apoptosis are regulated by EGFR, and (iii) the significance of endogenous TGF-a in regulating gastric and/or colonic mucosal EGFR tyrosine kinase and in turn, proliferation and apoptosis, and (B) To determine the role of ERRP in regulating EGFR and in turn, proliferation and apoptosis in the gastric and colonic mucosa during aging. This will be accomplished by generating ERRP fusion protein and studying the effect of ERRP on EGFR activation, proliferation and apoptosis in the gastric and colonic mucosa during advancing age. ERFORMANCE SITE(S) (organization, city, state) Research Service John D. Dingell VA Medical Center 4646 JohnR Detroit, MI 48201 KEY PERSONNEL ========================================Section End===========================================