BIOSYNTHETIC ACTIVITY OF THE CHOROID PLEXUS

脉络丛(CP)构成了血液的主要界面-- 脑脊液(CSF)屏障，负责分泌 很大一部分脑脊液。最近的工作证明了重要的 CP的生物合成活性，表明CP还发挥着 在测定脑脊液大分子含量方面起着至关重要的作用。我们(和 其他)已经证明了具体和丰富的合成 转甲状腺激素(TTR，前白蛋白)，一种甲状腺激素和 视黄醇，在CP上皮内。我们还描述了合成 胰岛素样生长因子II(IGF-II)，一种胎儿有丝分裂原 结构上与胰岛素原相似，由CP上皮和 成年大鼠脑内的软脑膜。信使核糖核酸的存在 对于转铁蛋白，铜蓝蛋白和β-preylod蛋白已经 报道，我们已经通过免疫组织化学显示，存在 CP中的其他几种特殊酶和血浆蛋白。 综上所述，这些数据表明，CP是一个重要的 大脑外部环境组成的决定因素。 我建议从三个主要方面进行调查，这些调查源于我们的 前期工作：1)成熟CP的基因表达。我们将扩大 研究了CP的生物合成谱系，从而产生了 CP表达的基因探针板。在选定的案例中(例如Ttr和IGF- Ii)，我们将开始研究它们的生理意义 中枢神经系统内合成。2)CP的发展研究。评审团 CP DNA探针将被用来研究猪的基因表达模式 发展CP。这项提议的一个主要焦点是试图发展 一种研究CP形态发生的体外系统。这个 我们可用的探针的特异性表明了一种新的方法来解决这个问题 问：通过共培养室管膜和软脑膜以及 试图模拟CP的分化，根据发病情况进行分析 从头开始合成Ttr。(3)脑膜瘤。CP基因小组 将被用于研究人类脑瘫肿瘤的基因表达 还有动物。人乳头状瘤及SV40/转基因小鼠模型的建立 多灶性CP乳头状瘤将研究向上或向下的模式- 受调控的基因。在相关情况下(例如IGF-II)，其他脑瘤将 也有待研究。在上面的所有内容中，正如我们之前的工作一样，经典 分子遗传学技术将得到大力强调的补充 形态学技术，包括免疫组织化学和原位 杂交。

The choroid plexus (CP) forms a major interface of the blood- cerebrospinal fluid (CSF) barrier and is responsible for the secretion of a large fraction of the CSF. Recent work has demonstrated important biosynthetic activities of the CP, suggesting that the CP also plays a vital role in determining the macromolecular content of the CSF. We (and others) have demonstrated the specific and abundant synthesis of transthyretin (TTR, prealbumin), a transport protein for thyroxine and retinol, within the CP epithelium. We have also described the synthesis of insulin-like growth factor II (IGF-II), a fetal mitogen bearing structural similarity to proinsulin, by the CP epithelium and leptomeningeal membranes of the adult rat brain. The presence of mRNA for transferrin, ceruloplasmin and the beta-preamylod protein have been reported, and we have shown, by immunohistochemistry, the presence of several other specialized enzymes and plasma proteins within the CP. Taken together, these data suggest that the CP is an important determinant of the composition of the external milieu of the brain. I propose to pursue three major lines of investigation deriving from our previous work: 1) Gene expression in the mature CP. We will expand the study of the biosynthetic repertoire of the CP, thereby generating a panel of CP-expressed gene probes. In selected cases (eg. TTR and IGF- II), we will begin to investigate the physiological significance of their intra-CNS synthesis. 2) Developmental studies of the CP. The panel of CP DNA probes will be used to study patterns of gene expression in the developing CP. A major focus of this proposal is an attempt to develop an in-vitro system for studying the morphogenesis of the CP. The specificity of our available probes suggests a novel approach to this question: by co-culturing ventricular ependyma and leptomeninges and attempting to simulate differentiation of the CP, as assayed by the onset of de novo TTR synthesis. 3) Neoplasia of the CP. The CP gene panel will be employed to study gene expression in tumors of the CP in humans and animals. Human CP papillomas and the SV40/transgenic mouse model of multifocal CP papillomas will be studied for patterns of up- or down- regulated genes. Where relevant (eg. IGF-II), other brain tumors will also be studied. In all of the above, as in our previous work, classic molecular gentic techniques will be complemented by a strong emphasis on morphological techniques, including immunohistochemistry and in situ hybridization.