PERINATAL MATURATION OF PITUITARY GROWTH HORMONE RELEASE

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Growth hormone (GH) is needed for fetal organ development, metabolic homeostasis in the newborn, and postnatal somatic growth. Despite its importance and the marked changes in GH secretion that characterize early mammalian development, the determinants of GH secretion during the perinatal period are not known. I found that the ability of the pituitary to secrete GH in response to classical GH regulatory agents including GH-releasing factor (GHRF) and somatostatin (SRIF) changes strikingly during early development. However, the cellular mechanisms responsible for this maturation of pituitary function are not known. Our preliminary studies indicate that GH release in response to protein kinase C (PKC) activators pituitary expression of PKC isotypes, and somatotroph [Ca2+]i signaling patterns undergoes marked change during perinatal development. Therefore, this proposal focuses on the hypothesis that maturation of pituitary somatotroph function during the perinatal period involves the development of key signal transduction loci-including expression of the GHRF receptor, generation of cAMP, PKC isotypes, and [Ca2+]i signalling. We will explore this hypothesis through four specific aims. The first focuses on the role of the GHRF receptor in regulating GH secretion during the perinatal period. We will determine the ontogeny of pituitary GHRF receptor mRNA expression in fetal, neonatal, juvenile, and adult rats; subsequently, we will evaluate the impact of altered expression of the GHRF receptor on GH secretion and growth in a transgenic model. In the second aim, we will determine whether the capacity of perinatal pituitaries to generate cAMP in response to GHRF and SRIF accounts for age-dependent GH release. The third aim focuses on PKC; we will determine the effects of acute and prolonged exposure to PKC activators on GH release, and will define pituitary expression of specific PKC isotypes during early development. Our fourth aim is to evaluate the regulation of free cytosolic Ca2+ ([Ca2+])i in perinatal somatotrophs by defining the effects of Ca2+ modifying agents on GH release, and by determining {Ca2+]i signalling patterns in individual pituitary cells using fura 2-based digital imaging microscopy. Our long term goal is to identify the mechanisms underlying the maturation of neuroendocrine control of GH secretion. This knowledge is necessary to understand the physiological determinants of GH release during early development and pathophysiology of GH secretory disorders. This project will define key cellular mechanisms that contribute to perinatal maturation of GH secretion, and will identify cellular loci at which developmental aberrations may lead to GH secretory disorders of childhood.