BIOLOGY AND PATHOLOGY OF A MODULATOR OF FGF

描述(由申请人提供)：成纤维细胞生长因子(成纤维细胞生长因子-1或-2)在成人大多数正常组织中存在显著浓度。然而，这些FGFs是以非活性状态固定在细胞外基质上的，人们对它们如何被溶解和激活以到达它们的细胞外受体知之甚少。动员这些生长因子的一种机制是通过与分泌的成纤维细胞生长因子结合蛋白(成纤维细胞生长因子结合蛋白或BP)结合。在我们以前的工作中，我们发现BP可以增强本地储存的、固定化的FGFs的活性，并且BP的表达可以支持肿瘤的生长和成纤维细胞生长因子-2阳性的非肿瘤细胞的血管生成。最近，我们在基因家族(BP2和BP3)中发现了与原始BP1具有相似活性的新成员。我们没有检测到BP1在正常成人组织和成年小鼠中的表达，但发现BP1在皮肤和肠道中上调，在不同癌症(结肠癌、乳腺癌、胰腺癌、鳞状细胞癌)的样本中发现BP1上调。我们假设与BP蛋白家族的相互作用影响FGFs的生物活性水平。根据我们的初步数据，我们推测不同的BPS对不同的FGFs的疗效会不同。初步数据表明，BP1增强了成纤维细胞生长因子-1和-2的活性，而抑制了成纤维细胞生长因子-4的活性。我们提出了以下具体目标：目的1.研究精选的BPS和FGFs的蛋白质相互作用结构域和体外功能。目的2.在致癌基因和癌基因模型中，研究在胚胎发生过程中选择BPS作为转基因基因对肿瘤进展的影响。目的3.研究所选BP基因缺失的影响。鸡胚胎和小鼠模型将被用于发育和肿瘤生物学研究。

DESCRIPTION (provided by applicant): Fibroblast growth factors (FGF-1 or -2) are present at significant concentrations in most normal tissues in the adult. However, these FGFs are immobilized in an inactive state on the extracellular matrix and it is only poorly understood how they are solubilized and activated to reach their extracellular receptors. One mechanism through which these growth factors can be mobilized is by binding to secreted binding proteins for FGF (FGF-BP or BP). In our previous work we showed that BP can enhance the activity of locally stored, immobilized FGFs and that expression of BP can support tumor growth and angiogenesis of FGF-2 positive non-tumorigenic cells. Recently we identified additional members in the gene family (BP2 and BP3) with similar activity as the original BP1. We did not detect BP1 mRNA in normal adult human tissues and adult mice but found that transformation upregulated BP1 in skin and gut and BP1 was found upregulated in samples from patients with different cancers (colon, breast, pancreatic, squamous cell). We hypothesize that the interactions with the BP family of proteins impacts on the biologic activity levels of FGFs. From our preliminary data we speculate that the efficacy of the different BPs will be different towards different FGFs. Preliminary data suggest that BP1 enhances FGF-1 and -2 activity whilst it inhibits FGF-4 activity. We propose the following specific aims: Aim 1. To study the protein interaction domains and in vitro function of selected BPs and FGFs. Aim 2. To study the impact of selected BPs as a transgene during embryogenesis and on tumor progression in carcinogen and oncogene models. Aim 3. To study the impact of deletion of selected BPs. Chick embryo and mouse models will be employed in developmental and tumor biology studies.