BIOSYNTHETIC ACTIVITY OF THE CHOROID PLEXUS

甲状腺素运载蛋白在血浆转运中发挥重要作用， 甲状腺素和视黄醇（维生素A），但其在中枢神经系统的精确功能 神经系统不清楚。 我们最近分离了一个人的cDNA克隆， 甲状腺素运载蛋白（TTR），并证明TTR信使的特异性存在 大鼠和人类中枢神经系统脉络丛中的RNA。 这是唯一分配给脉络丛的第一个肽。 这 建议将试图利用这一发现来研究监管， 脉络丛中的基因表达和 组织特异性基因 初步的免疫细胞化学数据表明， TTR在许多良性脉络丛肿瘤中可能不表达 （乳头状瘤）。 使用另一种脉络膜特异性探针的研究将 区分基因表达的特异性下调和普遍性下调。 免疫细胞化学和原位杂交技术将 因此可以用来研究大鼠和人脑切片， 局部合成的血管紧张素原、胰岛素和/或转铁蛋白，所有 作为另一种脉络膜特异性蛋白的候选者。 类似研究 将在SV 40诱导的脉络丛乳头状瘤组织上进行， 实验动物 从这些肿瘤中探测总基因组DNA， 从SV 40、TTR和任何其他脉络膜特异性克隆制备的cDNA探针 可能提供深入了解肿瘤发生机制和 脉络膜特异性基因的协调控制。 寻找一个可能的 调控元件将被几种分子遗传学方法所追求， 技术. 与此同时，我们将研究各种饮食的影响 和激素对TTR基因转录调控的影响， 通过关联TTR蛋白浓度，如通过 放射免疫分析，TTR mRNA水平通过北方分析评估， 原位杂交 由于维生素A和甲状腺缺乏， 中毒状态与良性的临床综合征有关 颅内高压，我们建议测量脑脊液TTR 浓度，以确定TTR是否介导CSF 生产和稳态。 此外，已将突变TTR单体 被鉴定为家族性淀粉样多发性神经病的病因。 我们 研究可能有助于阐明这种疾病的发病机制。

Transthyretin fulfills important functions in the plasma transport of thyroxine and retinol (vitamin A), but its precise function in the central nervous system is unclear. We recently isolated a cDNA clone for human transthyretin (TTR) and demonstrated the specific presence of TTR messenger RNA in rat and human choroid plexus within the central nervous system. This is the first peptide assigned uniquely to the choroid plexus. This proposal would attempt to exploit this finding to study the regulation of gene expression in the choroid plexus and the co-ordinate expression of tissue specific genes. Preliminary immunocytochemical data suggest that TTR may not be expressed in many benign human choroid plexus tumors (papillomas). Studies with another choroid-specific probe would distinguish specific from generalized down-regulation of gene expression. The techniques of immunocytochemistry and in-situ hybridization will therefore be employed to survey rat and human brain sections for evidence of site-specific synthesis of renin, insulin and/or transferrin, all candidates for being another choroid specific protein. Similar studies will be performed on tissue from SV40-induced choroid plexus papillomas in experimental animals. Probing total genomic DNA from these tumors with cDNA probes prepared from SV40, TTR and any other choroid-specific clone may provide insights into the mechanisms of tumorigenesis and the co-ordinate control of choroid-specific genes. The search for a possible regulatory element will be pursued by several molecular genetic techniques. Concomitantly, we shall study the effect of various dietary and hormonal manipulations on the regulation of TTR gene transcription in the rat by correlating TTR protein concentrations, as measured by radioimmunoassay, with TTR mRNA levels as assessed by Northern analysis and in-situ hybridization. Since both vitamin A and thyroid deficiency and toxic states are associated with the clinical syndrome of benign intracranial hypertension, we propose to measure cerebrospinal fluid TTR concentrations in this condition to ascertain whether TTR mediates CSF production and homeostasis. In addition, a mutant TTR monomer has been identified as the etiology of familial amyloidotic polyneuropathy. Our studies may help elucidate the pathogenetic basis of this disorder.