Hepatoma Derived Growth Factor & VSM Cell Proliferation

描述(申请人提供)：血管平滑肌细胞(SMC) 增殖是病理生理反应的中心组成部分。 受伤。肝癌衍生生长因子(HDGF)是一种强大的SMC有丝分裂原， 通常不存在于大鼠颈动脉中，但在 球囊损伤后新生内膜的核型。HDGF也存在于 人血管疾病与增殖细胞核抗原在人血管内皮细胞增殖中的共表达 人类动脉粥样硬化斑块，但HDGF产生SMC的机制 扩散是未知的。这在一定程度上是由于相当大的争议 关于生长因子的核心作用，总体上和在 尤其是血管壁。像HDGF一样，血管中的许多生长因子 WALL包括血小板衍生生长因子(PDGF)和成纤维细胞生长 因子(成纤维细胞生长因子)，是核靶向的。然而，增长的核心作用 因素，如果有的话，还没有得到证明。这笔赠款的总体目标是 建议阐明HDGF刺激SMC的核机制(S) 在体外增殖和对损伤的反应。在我们的初步研究中，我们 在假定的两部分核定位中发现单点突变 序列阻断HDGF核靶向和有丝分裂。我们现在也有 酵母双杂交筛选和免疫共沉淀(IP)研究的证据 HDGF结合了关键的核细胞周期调控蛋白p55cdc。基座 在这些研究的基础上，我们建议确定HDGF的调控机制 核进入；核进入是否对有丝分裂功能是必要的；以及 核功能是否是细胞周期控制蛋白的调节 P55cdc.拟议研究的意义在于，通过将人类发展筹资框架与 细胞核进入对细胞周期控制蛋白p55cdc的调节 HDGF核活动中的关键一步被揭示并聚集在一起 首次提出了生长因子在SMC中作用的核机制(S)。的确， 了解HDGF如何调节细胞增殖可能会提供额外的 对生长因子如何调控细胞生长的总体洞察。

DESCRIPTION (provided by the applicant): Vascular smooth muscle cell (SMC) proliferation is a central component of the pathophysiologic response to injury. Hepatoma derived growth factor (HDGF) is a potent SMC mitogen that is not normally present in the rat carotid, but becomes highly expressed in a nuclear pattern in the neointima after balloon injury. HDGF is also present in human vascular disease being co-expressed with PCNA in proliferating SMC in human atherosclerotic plaques, but the mechanisms by which HDGF produces SMC proliferation are unknown. This is due in part to the considerable controversy regarding the nuclear function of growth factors, in general and in the vascular wall in particular. Like HDGF, many growth factors in the vascular wall, including platelet derived growth factor (PDGF) and fibroblast growth factor (FGF), are nuclear targeted. However the nuclear function of growth factors, if any, has not been demonstrated. The overall goal of this grant proposal is to elucidate the nuclear mechanism(s) by which HDGF stimulates SMC proliferation in vitro and in response to injury. In our pilot studies, we found that single point mutations in a putative bipartite nuclear localization sequence block HDGF nuclear targeting and mitogenesis. We also now have evidence from a yeast two hybrid screen and co-immunoprecipitation (IP) studies that HDGF binds the key nuclear cell cycle regulatory protein p55cdc. Based upon these studies, we propose to determine the mechanisms regulating HDGF nuclear entry; whether nuclear entry is necessary for mitogenic function; and whether the nuclear function is regulation of the cell cycle control protein p55cdc. The significance of the proposed studies is that by linking HDGF nuclear entry to regulation of the cell cycle control protein p55cdc, a critical step in the nuclear action of HDGF is revealed and brings together for the first time the nuclear mechanism(s) of growth factor action in SMC. Indeed, understanding how HDGF regulates cell proliferation may provide additional insights into how growth factors regulate cellular growth in general.