GROWTH FACTOR ACTION AND AGING IN FIBROBLASTS

衰老与细胞增殖性下降有关 容量。在培养中，哺乳动物成纤维细胞经历了有限的 人口倍增的数量(老龄化)；这个数字 一般会随着年龄的增长而减少。其作用机制 对细胞衰老负有责任的人在很大程度上是未知的。 细胞增殖是由环境因素控制的，其中 多肽生长因子发挥着重要作用。现有证据 表明衰老细胞表现出的有缺陷的生长是 是生长因子后受体位置异常的结果， 一些与生长相关的基因可能会异常表达 在衰老的细胞中。该提案探讨了增长因素是如何- 产生的信号调节培养的人的特定基因 成纤维细胞活跃增殖或衰老的成纤维细胞。这个 主要感兴趣的基因包括原癌基因c-fos、c-fos、 MYC和c-ras、鸟氨酸脱羧酶和两个未知基因 其表达是生长因子诱导的函数(JE和JB)。 这些基因可能具有不同的功能，而且很可能 在不同的位置调节(转录前或转录后)，由 生长因子产生的信号。 我们将通过增长来确定监管的程度和水平 因子信号，我们将确定一个或多个受体后 在细胞衰老过程中，系统会发生变化，导致 某些基因调控的特定变化。这些研究 旨在提供一个分子基础来建立我们的 早期对细胞增殖控制的认识 传代人成纤维细胞和细胞衰老过程中。

Aging is associated with a decline in cellular proliferative capacity. In culture, mammalian fibroblasts undergo a limited number of population doublings (senescence); this number generally decreases with increasing age. The mechanisms responsible for cell senescence are largely unknown. Cell proliferation is governed by environmental factors, of which polypeptide growth factors play a major role. Current evidence suggests that the defective growth shown by senescent cells is the result of an abnormality at a post-growth factor receptor site, and that some growth-related genes may be abnormally expressed in senescent cells. This proposal explores how growth factor- generated signals modulate specific genes in cultured human fibroblasts undergoing active proliferation or senescence. The genes of primary interest include the proto-oncogenes c-fos, c- myc and c-ras, ornithine decarboxylase, and two genes of unknown function (JE and JB) whose expression is growth factor-inducible. These genes probably serve different functions, and are likely regulated at different sites (pre- or post-transcriptional) by growth factor-generated signals. We will define the extent and levels of regulation by growth factor signals, and we will determine one or more post-receptor systems are altered during cellular senescence, resulting in specific changes in the regulation of certain genes. These studies are designed to provide a molecular basis on which to build our understanding of the control of cell proliferation both in early passage human fibroblasts and during cellular senescene.