Myelination of axons is a complex process that has received the attention of morphologists and biochemists. Considerable progress has been made in the study of specific protein components of myelin by using molecular genetic methods. The genes coding for myelin basic protein (MBP), proteolipid protein (PLP), and PO glycoprotein have been studied by other investigators. These proteins may serve a structural role, although no specific function has been ascribed to any of them. P2, a basic proteins found primarily in the peripheral nervous system (PNS), belongs to a homologous family of fatty acid binding proteins (FABPs) which includes rat liver FABP, rat intestinal FABP, the retinol binding proteins, and an adipocyte lipid binding protein. These proteins have a specific affinity for certain fatty acids, and may be important in intercellular and intracellular fatty acid transport. P2 may have a similar function in myelin producing cells. P2 has also been implicated in the production of experimental allergic neuritis (EAN), a model for the Guillain-Barre syndrome. The long term objective of this project is a complete molecular analysis of the P2 gene and its regulation. This proposal seeks specifically (1) to characterize the cDNA clone encoding myelin P2 protein, (2) to study the developmental profile of P2 mRNA levels by Northern blot analysis and in situ hybridization, (3) to determine the structure of the P2 gene, (4) to clone and characterize the promoter region by sequence analysis and deletion of specific fragments, and (5) to study the function of P2 protein using binding studies of specific long-chain fatty acids, and by inducing the transcription of anti-sense mRNA in Schwann cells, capable of blocking the translation of endogenous P2 mRNA. These studies will (a) contribute to our understanding of the function of P2 (making it the first myelin specific protein with known metabolic activity), (b) enhance our knowledge of the process of myelination, and (c) provide molecular probes for the study of dysmyelinating disorders, such as Guillain-Barre syndrome or adrenoleukodystrophy.
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