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（FGF-1或-2）以显著浓度存在于成人的大多数正常组织中。然而，这些FGF以非活性状态固定在细胞外基质上，并且仅对它们如何溶解和活化以到达其细胞外受体知之甚少。这些生长因子可被动员的一种机制是通过与分泌的FGF结合蛋白（FGF-BP或BP）结合。在我们以前的工作中，我们表明BP可以增强局部储存的固定化FGF的活性，并且BP的表达可以支持FGF-2阳性非致瘤细胞的肿瘤生长和血管生成。最近，我们在基因家族（BP 2和BP 3）中发现了与原始BP 1具有相似活性的其他成员。我们在正常成人组织和成年小鼠中没有检测到BP 1 mRNA，但发现转化上调了皮肤和肠道中的BP 1，并且发现BP 1在不同癌症患者（结肠癌、乳腺癌、胰腺癌、鳞状细胞癌）的样品中上调。我们假设与BP家族蛋白质的相互作用影响FGF的生物活性水平。根据我们的初步数据，我们推测不同BP对不同FGF的疗效将不同。初步数据表明，BP 1增强FGF-1和-2活性，同时抑制FGF-4活性。我们提出以下具体目标：目标1。研究所选BPs和FGF的蛋白质相互作用结构域和体外功能。目标2.在致癌物和癌基因模型中研究所选BP作为胚胎发生期间的转基因以及对肿瘤进展的影响。目标3。研究删除选定BP的影响。鸡胚和小鼠模型将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.