BIOSYNTHETIC ACTIVITY OF THE CHOROID PLEXUS

转甲状腺激素在血浆转运中发挥重要作用 甲状腺素和视黄醇(维生素A)，但其在中枢的精确功能 神经系统尚不清楚。我们最近分离了一个人的cdna克隆。 转甲状腺激素受体(TTR)，并证明了TTR信使的特异性存在 中枢神经系统内大鼠和人脉络丛中的RNA。 这是第一个唯一分配给脉络丛的多肽。这 提案将试图利用这一发现来研究对 基因在脉络丛中的表达及相关基因的协同表达 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)。另一种脉络膜特异性探针的研究将 区分基因表达下调的特异性和广泛性。 免疫细胞化学和原位杂交技术将 因此被用来调查大鼠和人脑切片以寻找证据 肾素、胰岛素和/或转铁蛋白的位置特异性合成 是另一种脉络膜特异性蛋白质的候选者。类似的研究 将对SV40诱导的脉络丛乳头状瘤组织进行手术 实验动物。从这些肿瘤中探测总基因组DNA 从SV40、TTR和任何其他脉络膜特异性克隆制备的cDNA探针 可能对肿瘤发生的机制和肿瘤的 脉络膜特异基因的协调控制。寻找一种可能的 调控元件将被几个分子遗传所追求 技巧。与此同时，我们将研究各种饮食的效果 激素调控TTR基因转录的研究进展 通过关联TTR蛋白浓度，如通过 放射免疫分析，用Northern分析和 原位杂交。因为维生素A和甲状腺缺乏症 中毒性状态与良性疾病的临床综合征有关 高颅压时，我们建议测量脑脊液TTR值 在这种情况下的浓度以确定TTR是否介导脑脊液 生产和动态平衡。此外，一种突变的Ttr单体已经被 被确认为家族性淀粉样多发性神经病的病因。我们的 研究可能有助于阐明这种疾病的发病基础。

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.