The long-range objective of this research program is to define chemical properties of nerve and other tissues which exert a trophic influence on the development of muscle. Our recent studies have demonstrated that transferrin (Tf) is present in adult avian sciatic nerves and has profound myotrophic effects in vitro. While Tf is required by virtually all types of cells in tissue culture, its precise biological role has not been defined. In particular, little is known about the effects of Tf on cellular metabolism and gene expression in developing and adult muscles. Thus, the immediate goals of this proposal are to clarify the roles of Tf and the Tf/receptor interaction in muscle metabolism and to investigate the mechanism by which Tf influences muscle development.
Three specific aims are proposed. 1) To study the role of Tf and its receptors in developing muscle in vitro and in vivo. Our studies demonstrate that Tf receptors are present on developing muscle and that labeled Tf is specifically accumulated by this tissue. Experiments will now be conducted to determine the specific binding and uptake of Tf, to purify Tf receptors and to produce specific antibodies to them and to demonstrate the number and distribution of Tf receptors in developing and adult muscle. Antibodies to Tf receptors will also be used to determine the conseqences of receptor blockade. 2) To examine the role of Tf in the gene expression of the glycolytic enzyme, aldolase. Recent data show that Tf induces a 2-5-fold increase in the muscle-specific form of adolase, A4. The neuronal (C4) and myogenic forms of aldolase will be purified and antibodies to these isoenzymes will be produced. The role of Tf in the expression of aldolase isoenzymes will be determined by blocking the Tf receptors with specific antibodies during muscle development. 3) To investigate the regulation of Tf receptor expression by such influences as neural tissue, innervation and muscle activity. These studies will involve: (i) co-cultures of nerve and muscle; (ii) electrical stimulation of cultured muscle; and (iii) denervation of wing muscles in ovo. The results of these studies will yield fundamental information regarding the physiological action of Tf in muscle development. Such information can contribute to an understanding of factors underlying degenerative diseases of muscle such as muscular atrophy and muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015013-09
Application #
3395878
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1979-01-01
Project End
1988-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Oh, T H; Markelonis, G J; Von Visger, J R et al. (1995) Acidic pH rapidly increases immunoreactivity of glial fibrillary acidic protein in cultured astrocytes. Glia 13:319-22
Von Visger, J R; Yeon, D S; Oh, T H et al. (1994) Differentiation and maturation of astrocytes derived from neuroepithelial progenitor cells in culture. Exp Neurol 128:34-40
Oh, Y J; Markelonis, G J; Oh, T H (1993) Effects of interleukin-1 beta and tumor necrosis factor-alpha on the expression of glial fibrillary acidic protein and transferrin in cultured astrocytes. Glia 8:77-86
Oh, Y J; Francis, J W; Markelonis, G J et al. (1992) Interleukin-1-beta and tumor necrosis factor-alpha increase peripheral-type benzodiazepine binding sites in cultured polygonal astrocytes. J Neurochem 58:2131-8
Jeong, S J; Oh, T H; Markelonis, G J (1991) A neurite-promoting factor from muscle supports the survival of cultured chicken spinal motor neurons. J Neurobiol 22:462-74
Oh, Y J; Markelonis, G J; Oh, T H (1991) Immunocytochemical localization of mitochondrial malate dehydrogenase in primary cultures of rat astrocytes and oligodendrocytes. J Histochem Cytochem 39:681-8
Oh, T H; Markelonis, G J; Dion, T L et al. (1988) A muscle-derived substrate-bound factor that promotes neurite outgrowth from neurons of the central and peripheral nervous systems. Dev Biol 127:88-98
Oh, T H; Rosser, B W; Shear, C R et al. (1988) Immunocytochemical localization of aldolase in normal, denervated, and dystrophic chicken muscles. J Histochem Cytochem 36:227-35
Markelonis, G J; Oh, T H; Dion, T L et al. (1988) Localization of transferrin within the developing vertebrate nervous system. Rev Neurol (Paris) 144:648-55

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