AGING GUT--REGULATION OF CELL PROLIFERATION

描述（改编自申请人摘要）：PI已 在Fischer-344大鼠中证实， 随着年龄的增长，胃里的脂肪含量也会增加。 其他人也表现出类似的 老年啮齿类动物小肠和大肠的增殖增加。 这种现象背后的机制尚不清楚。 发表作品 1989年由主要研究者进行的研究表明， 胃粘膜对EGF和TGF-α作用的剂量反应 这些肽的曲线向右移动， 对青年大鼠胃的刺激对老年大鼠胃的抑制作用。 伴随着这些变化，主要研究者和合作者 已经注意到EGF-R酪氨酸激酶活性的增加， 许多非受体细胞蛋白的磷酸化水平升高， 特别是Mr为55 Kda的蛋白质（命名为pp 55）。 拟议 研究旨在阐明EGF家族肽的作用， 确定pp 55的作用。 主要研究者计划：（a）研究是否增加 敏感性是由于EGF与受体（EGF-R）的结合增加 或/和受体后变化;和（B）评价增加的 EGF的剂量与通过施用EGF的免疫中和 抗体的 在一系列不同目的的研究中，研究人员 希望了解新的酪氨酸激酶（pp 55）的功能， 表皮生长因子受体与表皮生长因子受体无关， 各种条件下，特别是在老化的胃粘膜。 他们的计划 分离编码pp 55的cDNA克隆，完成核苷酸测序， 并且当全长转录本可用时， 杆状病毒基因表达系统中的转录本。 他们的表现 在老年大鼠的结肠粘膜中进行了类似的研究， 更大的刺激EGF-R酪氨酸激酶活性在老年动物。

DESCRIPTION (Adapted from the Applicant's Abstract): The PI has demonstrated in the Fischer-344 rat that proliferation of epithelial cells in the stomach increases with advancing age. Others have shown similar increased proliferation in the small and large intestine of older rodents. The mechanism underlying this phenomenon is not known. Work published since 1989 by the Principal Investigator has shown an increase in the sensitivity of the gastric mucosa to the action of EGF and TGF-a since the dose response curve for these peptides was shifted to the right and doses that were stimulating in the stomach of young rats were inhibitory in aging rats. Accompanying these changes, the Principal Investigator and collaborators have noted an increase in EGF-R tyrosine kinase activity and a concordant rise in the phosphorylation of a number of non-receptor cellular proteins, particularly a protein with an Mr of 55 Kda (named pp55). The proposed studies aim to clarify the effects of the EGF family of peptides and to determine the role of pp55. The Principal Investigator plans: (a) to study whether increased sensitivity is due to increased binding of EGF to the receptor (EGF-R) or/and post receptor changes; and (b) to evaluate effects of increasing doses of EGF versus immunoneutralization by the administration of EGF antibodies. In a separate series of studies with separate purposes, the investigators wish to understand the functions of the novel tyrosine kinase (pp55) that is not associated with the EGF receptor and appears to be stimulated under a variety of conditions, particularly in the aging gastric mucosa. Their plan is to isolate the cDNA clones encoding pp55, complete nucleotide sequencing and when a full length transcript is available, to overexpress this transcript in the baculovirus gene expression system. They have performed similar studies in the colonic mucosa of aging rats in which they find greater stimulation of EGF-R tyrosine kinase activity in older animals.