GROWTH FACTOR ACTION AND AGING IN FIBROBLASTS

衰老与细胞增殖能力下降有关， 容量 在培养中，哺乳动物成纤维细胞经历有限的 人口老龄化（衰老）的数量;这个数字 一般随着年龄的增长而减少。 的机制 导致细胞衰老的原因还不清楚。 细胞增殖受环境因素控制，其中 多肽生长因子起主要作用。 目前的证据 表明衰老细胞所表现出的生长缺陷是 由于后生长因子受体位点的异常， 一些与生长相关的基因可能会异常表达 在衰老细胞中。 这份提案探讨了增长因素- 产生的信号调节培养的人类中的特定基因 经历活跃增殖或衰老的成纤维细胞。 的 主要感兴趣的基因包括原癌基因c-fos，c-fos和c-fos。 myc和c-ras，鸟氨酸脱羧酶，以及两个未知的基因 功能（JE和JB），其表达是生长因子诱导的。 这些基因可能具有不同的功能， 在不同的位点（转录前或转录后）受到 生长因子产生的信号。 我们将通过增长来定义监管的范围和水平 因子信号，我们将确定一个或多个后受体 系统在细胞衰老过程中发生改变， 某些基因调控的特定变化。 这些研究 是为了提供一个分子基础， 了解细胞增殖的控制， 传代人成纤维细胞和细胞衰老期间。

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.