The specific aim of this application focuses on the regulation of myelination by thyroid hormone, glucocorticoid hormone, and retinoic acid, three potent regulators of development which tend to carry out their regulation in a cooperative manner. Their role in the regulation of myelination will be studied in oligodendrocytes dissociated from cerebra and grown in cultures whose efficacy for studying myelination and its regulation has been established. Very little is known about how retinoic acid and retinol function as regulators of the differentiation of single nerve cells. No studies have been carried out on the regulation by retinoids of the production of myelin by oligodendroglia. Therefore our first set of experiments investigates the regulation of myelination by retinoids and the degree of cooperativity between retinoic acid, hydrocortisone and thyroid hormone in this regulation. These studies will examine the optimum conditions under which retinoic acid and retinol cause oligodendroglia to differentiate; the extent that oligos depend on astroglia to metabolize retinol to retinoic acid; the regulation of retinoid cellular binding proteins (CRBP and CRABP) and their nuclear receptor proteins (RAR-alpha and RAR-beta); and the brain cell-type (oligo, neuron, and astroglia) in which these proteins exist. The second set of investigations are on the regulation of sulfolipid metabolism by hydrocortisone (HC), thyroid hormone (T3), and retinoic acid (RA). Both T3 and HC cooperatively stimulate myelin sulfolipid accumulation; T3 by stimulating sulfolipid synthesis and HC by inhibiting its degradation by arylfulfatase A. HC inhibits ASA by decreasing the number of ASA molecules. To be studied is the mechanism by which HC decreases the number of molecules of ASA; the function of RA in stimulating sulfolipid accumulation; and the degree of sulfolipid accumulation may be affected by sphingolipid activating protein-1 concentration and its regulation by HC, T3, and RA. The third set of experiments are investigations on the degree of cooperativity between T3 and HC needed to express myelin basic protein (MBP). HC can not stimulate myelin basic protein synthesis in the absence of T3. But HC can stimulate MBPmRNA levels to increase in the absence of T3. Therefore studies will determine how and why T3 is required for this post-transcriptional event. These studies provide insight into how three potent effectors of development regulate myelin membrane synthesis, a malfunction of which can lead to a number of severe pathological conditions.
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