AGING GUT--REGULATION OF CELL PROLIFERATION

肠道老化——细胞增殖的调节

• 批准号: 2002255
• 负责人: ADHIP P. N. MAJUMDAR
• 金额: $ 15.2万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2002255
• 关键词: Baculoviridae; aging; antibody; cell growth regulation; cell proliferation; complementary DNA; enzyme activity; epidermal growth factor; gastric mucosa; growth factor receptors; laboratory rat; nucleic acid sequence; phosphorylation; protein tyrosine kinase; receptor binding; receptor expression; transforming growth factors

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.

描述（改编自申请人的摘要）：PI 已 在 Fischer-344 大鼠中证明上皮细胞增殖 胃里的东西随着年龄的增长而增加。 其他人也表现出类似的情况 年长啮齿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。 自此发表的作品 1989年首席研究员的研究表明敏感性有所增加 自剂量反应以来胃粘膜对 EGF 和 TGF-a 作用的影响 这些肽的曲线向右移动，剂量为 对年轻大鼠的胃有刺激作用，但对老年大鼠的胃有抑制作用。 伴随这些变化，首席研究员和合作者 注意到 EGF-R 酪氨酸激酶活性的增加和一致 许多非受体细胞蛋白的磷酸化增加， 特别是 Mr 为 55 Kda 的蛋白质（称为 pp55）。 拟议的 研究旨在阐明 EGF 肽家族的作用并 确定pp55的作用。 首席研究员计划：(a) 研究是否增加了 敏感性是由于 EGF 与受体 (EGF-R) 的结合增加所致 或/和受体改变后； (b) 评估增加的影响 EGF 剂量与 EGF 免疫中和作用的比较 抗体。 在具有不同目的的一系列单独研究中，研究人员 希望了解新型酪氨酸激酶 (pp55) 的功能 与 EGF 受体无关，并且似乎在 多种病症，特别是老化的胃粘膜。 他们的计划 是分离编码pp55的cDNA克隆，完成核苷酸测序 当有完整的转录本时，要过度表达这一点 杆状病毒基因表达系统中的转录本。 他们表演过 对衰老大鼠的结肠粘膜进行了类似的研究，他们发现 对老年动物的 EGF-R 酪氨酸激酶活性有更大的刺激。