AGING OF MOUSE MAMMARY CELLS

计划中的实验侧重于细胞和组织调节的差异。 在年轻和衰老的小鼠乳腺上皮之间。使用塑料 能够持续、局部、体内释放生物活性的植入物 分子，我们已经证明了局部升高的环腺苷 一磷酸(CAMP)水平将重新启动DNA合成，细胞分裂 老年腺的正常形态发生已经耗尽了它的正常 增长潜力。这些结果强烈地表明，衰老的 表型是由于调节功能障碍(S)，而不是一般 细胞退化。我们的中心假设是，长期接触 到天然的有丝分裂原会产生特定的病变，导致 细胞对这些有丝分裂原的反应能力不可逆转的下降。 使用体内和体外方法的组合，以下是 问题将被调查：1.什么是限制和特征 霍乱毒素刺激下的cAMP反应？衰老的组织会生长吗？ 只要霍乱毒素还存在？夏令营的延长时间 刺激，以及剂量-反应将被研究。 2.天然的、cAMP活性的有丝分裂原可能与什么有关 乳房老化？提出了几条初步证据。 花生四烯酸代谢产物对乳腺的强烈调节作用 成长。这些药剂在衰老和年轻人成长过程中的作用 将对腺体进行调查，并将生长效应与 CAMP和腺苷环化酶水平。 3.表皮生长因子(EGF)在乳腺衰老中的作用？EGF 对培养中的乳腺细胞是有丝分裂的，我们的初步结果 表明在体内具有生长调节作用。使用培养的细胞和 植入技术，我们将研究EGF在生长和发育中的作用 幼腺的形态发生，并研究有丝分裂的可能丧失 对衰老细胞的有效性。

The proposed experiments focus on differences in cell and tissue regulation between young and senescent mouse mammary epithelium. Using plastic implants capable of sustained, local, in vivo release of bioactive molecules, we have demonstrated that locally elevated cyclic adenosine monophosphate (cAMP) levels will reinitiate DNA synthesis, cell division and normal morphogenesis in aged gland which has depleted its normal potential for growth. These results strongly suggest that the senescent phenotype is due to a regulatory dysfunction(s) rather than general cellular deterioration. Our central hypothesis is that prolonged exposure to natural mitogens produces specific lesions that result in an irreversible decline in the cell's ability to respond to these mitogens. Using a combination of in vivo and in vitro methods, the following questions will be investigated: 1. What are the limits and characteristics of the cholera toxin-stimulated, cAMP response? Will senescent tissue grow so long as cholera toxin is present? The extended time-course of cAMP stimulation, as well as the dose-response will be studied. 2. What are the natural, cAMP-active mitogens possibly implicated in mammary aging? Several lines of preliminary evidence are presented strongly implicating arachidonic acid metabolites as regulators of mammary growth. The role of these agents in both aging and the growth of young gland will be investigated, and growth effects will be correlated with levels of cAMP and adenylate cyclase. 3. What is the role of epidermal growth factor (EGF) in mammary aging? EGF is mitogenic for mammary cells in culture, and our preliminary results indicate a growth-regulatory role in vivo. Using both cultured cells and implant techniques, we will study the role of EGF in growth and morphogenesis of young gland, and investigate possible loss of mitogenic effectiveness in senescent cells.