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.
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