POMC EXPRESSION AND PROCESSING IN FETAL SHEEP PITUITARY

超出提供的空间。该提案的目的在于调节妊娠晚期绵羊胎儿肾上腺皮质糖皮质激素的生物合成。在胚胎绵羊中，血浆皮质醇浓度在妊娠的最后三周(出生=148天)呈指数级增加，从而产生一个可存活的新生儿。具体目标1将决定垂体前叶促肾上腺皮质激素的POMC加工作为促肾上腺皮质激素表型的功能。POMC的处理将在表达CRF)受体和/或AVP受体(V1b)的皮质激素亚群中进行研究。由于去往垂体前叶的PVN神经内分泌信号的中断阻止了肾上腺皮质的成熟，因此将研究POMC处理的神经肽调节。我推测：1)CRF通过C反应蛋白中的前激素转换酶1(PCI)诱导POMC向ACTH|.39的转化。受体表达皮质激素，2)没有CRF，POMC不被处理为ACTH|39，3)糖皮质激素抑制ACTH，.39生物合成和4)CRF减弱糖皮质激素对POMC处理的糖皮质激素抑制。特异性目标2将确定胎儿肾上腺皮质细胞对ACTH^g、22 kDa proACTH和POMC的反应机制。在成人中，ACTH，.39通过MC2R调节肾上腺皮质类固醇激素的生成。结果表明，MC2R、MC1R和MC5R在胎羊肾上腺皮质均有表达。假设MC2R、MC5R和MC1R对ACTH和ACTH前体具有不同的药理学特征，并且这些受体表达的发育变化对肾上腺皮质的发育至关重要。而MC2R对ACTH有很高的选择性]。39，MC5R识别多种黑素皮质素多肽和潜在的ACTH加工中间体，并提出了一种ACTH1.39，POMC，22 kDa Pro ACTH对胎儿肾上腺皮质调节的差异性调节机制。特异目的3是确定刺鼠基因在肾上腺皮质成熟中的作用。我们发现，在绵羊胎儿肾上腺皮质中表达的刺鼠基因编码MC2R和MC1R的强效拮抗剂(ASIP)，但不编码MC5R。假设ASIP拮抗ACTH，_39促进类固醇激素的生成，并且在妊娠期间ASIP的表达下降允许肾上腺皮质在低PM浓度的ACTH/_3y存在下成熟。尽管在早产儿的治疗和存活率方面取得了进展，但在美国、加拿大或其他发达国家，早产儿的患病率(~10%)并没有下降。早产仍然是婴儿死亡的主要原因。确定启动正常足月分娩和分娩的机制将导致制定更好的预防早产战略。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. The aims of this proposal focus on regulation of adrenocortical glucocorticoid biosynthesis in the late gestation sheep fetus. In fetal sheep, plasma cortisol concentrations increase exponentially during the final three weeks of gestation (birth =148 days) resulting in delivery of a viable neonate. Specific Aim 1 will determine POMC processing in anterior pituitary corticotropes as a function of corticotrope phenotype. POMC processing will be studied in corticotrope subpopulations expressing the CRF) receptor, AVP receptor (Vlb) or both receptors. Since disruption of the PVN neuroendocrine signal to the anterior pituitary prevents adrenocortical maturation, neuropeptide regulation of POMC processing will be examined. I hypothesize that 1) CRF induces processing of POMC to ACTH|.39 via prohormone convertase 1 (PCI) in CRP! receptor expressing corticotropes, 2) without CRF, POMC is not processed to ACTH|_39, 3) glucocorticoids suppress ACTH,.39 biosynthesis and 4) CRF attenuates glucocorticoid inhibition of POMC processing. Specific Aim 2 will determine mechanisms via which fetal adrenocortical cells respond to ACTH^g, 22 kDa proACTH and POMC. In adults, ACTH,.39 regulates adrenocortical steroidogenesis via the MC2R. Our data demonstrates that MC2R, MC1R and MC5R are expressed in the adrenal cortex of fetal sheep. / hypothesize that MC2R, MC5R and MC1R display distinct pharmacological characteristics for ACTH and ACTH precursors, and that developmental changes in the expression of these receptors is critical for adrenocortical development. While the MC2R is highly selective for ACTH].39, the MC5R recognizes multiple melanocortin peptides and potentially ACTH-processing intermediates and presents a mechanism for the differential regulation of fetal adrenocortical regulation by ACTHi.39, POMC, 22 kDa pro ACTH. Specific aim 3 is to identify the role of the agouti gene in adrenocortical maturation. We have found that the agouti gene-, which encodes for a potent antagonist (ASiP) of MC2R and MC1R but not MC5R, is expressed in ovine fetal adrenal cortex. / hypothesize that ASIP antagonizes ACTH,_39 stimulated steroidogenesis and that declining expression of AsiP during gestation allows adrenocortical maturation in the presence of low pM concentrations ofACTH/_3y. Despite advances in the treatment and survival rate of preterm infants, the prevalence of preterm birth (~ 10 %) has not declined in the U.S.A., Canada or other developed countries. Premature birth continues to be a major cause of infant mortality. Identifying mechanisms initiatingthe onset of normal term labor and delivery will lead to the development of better strategies for preventing premature birth. PERFORMANCE SITE ========================================Section End===========================================