The objective of our proposed studies is to obtain a more complete understanding of how hormones and (GFs) function to regulate growth and differentiation of rats in different stages of their development. The major hypothesis being tested is that the dependence on and responsiveness to hormones and growth factors change with development from the embryonic to the juvenile or subadult period. Aspects of a related postulate, the somatomedin (Sm) hypothesis, will also be evaluated. The research to be conducted can be placed in 4 related areas: 1. Regulation of the growth and differentiation of embryonic and fetal tissues in vivo by GFs and hormones. 2. Control of growth of cartilage and muscle in the hindlimb of juvenile (i.e. month old) rats by hormones and GFs. 3. Regulation of hepatic secretion of insulin- like growth factor-I (IGF-I). 4. Analysis of the changing dependence or responsiveness of tissues on hormones or GFs that occurs during development between the infant (i.e. 6 day old) and juvenile periods in the rat. The first 3 of these areas will involve chronic infusion of hormones, GFs or antisera to GFs into blood vessels using catheters attached to osmotic minipumps. The experiments on control of growth of embryos and fetal tissues will involve bilateral transplantation of 10 day rat embryos or 15 day fetal paws under the kidney capsule of juvenile or adult rats of the same inbred strain. The effects of GFs, hormones and antisera to the GFs on the growth and differentiation of these embryos will be studied by infusing them into the right renal artery. The effects of hormones and GFs on growth of cartilage and muscle will be determined by infusing them into the right common iliac artery (which supples blood to one hindlimb) of hypophysectomized (Hx) month old rats. Antibodies to the GFs will be infused in the same artery of rapidly growing rats of the same age. The direct effects of hormones (insulin, GH, T4 and corticosterone) on hepatic secretion of IGF-I in vivo will be determined by infusing them into the hepatic portal vein of Hx rats. Effects will be assessed by measuring serum IGF-I levels, tail growth and width of the tibial epiphyseal plate. Differences in hormonal dependence and responsiveness for growth between 6 day and 30 day old rats will be analyzed. Temporal changes in serum IGF-I levels (and possibly other growth factors) will be measured after Hx and the effects of GH and T4 on serum levels of insulin, IGF-I and GFs will be determined. The possibility that hormones and GFs in milk support growth of suckling rat pups will also be studied.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Endocrinology Study Section (END)
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University of California Berkeley
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Rodgers, B D; Bautista, R M; Nicoll, C S (1995) Regulation of insulin-like growth factor-binding proteins in rats with insulin-dependent diabetes mellitus. Proc Soc Exp Biol Med 210:234-41
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Denver, R J; Nicoll, C S (1994) Pancreatic hormones differentially regulate insulin-like growth factor (IGF)-I and IGF-binding protein production by primary rat hepatocytes. J Endocrinol 142:299-310
Rodgers, B D; Lau, A O; Nicoll, C S (1994) Hypophysectomy or adrenalectomy of rats with insulin-dependent diabetes mellitus partially restores their responsiveness to growth hormone. Proc Soc Exp Biol Med 207:220-6
Kelley, K M; Gray, E S; Siharath, K et al. (1993) Experimental diabetes mellitus in a teleost fish. II. Roles of insulin, growth hormone (GH), insulin-like growth factor-I, and hepatic GH receptors in diabetic growth inhibition in the goby, Gillichthys mirabilis. Endocrinology 132:2696-702
Hebert, N J; Kim, J H; Lin, R J et al. (1993) Restoration of lactation in bromocriptine-treated rats by prolactin replacement: comparison of constant versus pulsatile infusion and intrahepatic versus intrajugular routes of delivery. J Endocrinol Invest 16:29-35
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