A research program is proposed to investigate in detail the pathogenic mechanisms underlying the Portuguese type of familial amyloidotic polyneuropathy (FAP). This investigation also aims to acquire fundamental new information on the function of transthyretin (TTR) in the nervous system. The results should be relevant for the physiology of the nervous system and provide suggestions for future therapeutic approaches to FAP. Two major projects are proposed. Project One, on the intervening factors in the mechanisms of pathogenesis of FAP, aims to explore the influence of the mutant TTR found in FAP in the etiology of the disease. Studies are proposed to produce a specific monoclonal antibody directed at the mutant TTR and to develop an accurate immunoassay to measure the levels of the mutant TTR in biological specimens. This immunoassay would then be used in a variety of clinical studies to obtain new information about the pathophysiology and pathogenesis of FAP. A large and unique population of patients and carriers of the mutant gene is available in Portugal for these studies. Other studies will aim to localize the mutant TTR in tissues, and to search for DNA polymorphisnes in or adjacent to the TTR gene associated with variations in clinical expression of FAP. The general goal of Project Two is to explore in detail the function and metabolism of TTR in the nervous system. Studies are proposed that aim to: (1) quantitate TTR in the peripheral nerve; (2) explore the distribution and metabolism of TTR in the nervous system (in particular to explore the transfer of TTR from CSF to nerve, and the tissue sites of catabolism of CSF-derived TTR); (3) search for the binding of TTR to components of peripheral nerves; and (4) search for binding of TTR to specific binding sites/receptors of intact.
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