Transthyretin (TTR) is a thyroid hormone transport protein that is secreted by hepatocytes into the serum and by the choroid plexus epithelium into the cerebral spinal fluid. In the adult mammal the TTR gene is highly expressed in only these two cell types; the cis-acting elements required for its expression in each tissue are not identical, indicating an interesting degree of complexity. This proposal aims to identify the regulatory mechanisms that underlie multi-tissue and temporal regulation of the TTR gene in mice. Since much is already known about TTR expression in liver, extending the study to the choroid plexus will illuminate how one gene expressed from a single promoter is regulated in two distinct cell types. Thus, by studying the details of TTR gene control, the investigator may uncover mechanisms that apply more broadly to the important problem of differential gene control. Beyond the basic interest in gene regulation, further understanding of TTR regulation should provide insight into the TTR related human genetic disorder, familial amyloidotic polyneuropathy (FAP). The project's specific goals are to: (I) Determine the cis-acting elements required for choroid plexus expression. A combination of chromatin analyses, cell culture and transgenic mouse manipulation will be employed. (II) Identify putative choroid plexus specific trans-regulatory proteins. After defining the cis-acting controls for choroid plexus expression the investigator will search for the cognate binding proteins using well-differentiated mouse choroid plexus papillomas as an abundant source of nuclear proteins. (III) Analyze the temporal and fetal specific signals for TTR expression. Existing transgenic mice carrying various portions of TTR upstream sequence will be analyzed to determine whether the appropriate temporal and fetal specific cues are present. (IV) Generate an animal model for FAP. FAP is a dominant human disorder that correlates with a single amino acid change in TTR. The investigator will try to make use of the findings on TTR regulation to devise a transgenic mouse model for FAP. The role of choroid plexus TTR in FAP will be of particular interest.
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