Molecular Genetics of the HPA(I) Axis

HPA(I) 轴的分子遗传学

• 批准号: 6417796
• 负责人: PHILLIP B DANIELSON
• 金额: $ 13.14万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6417796
• 关键词: Cushing's syndrome; Osteichthyes; adrenocorticotropic hormone; aging; corticotropin releasing factor; developmental genetics; disease /disorder model; gene expression; hormone regulation /control mechanism; hypercortisolism; hypothalamic hormones; hypothalamic pituitary adrenal axis; immunocytochemistry; model design /development; molecular cloning; molecular genetics; molecular pathology; neurogenetics; neuroregulation; nucleic acid sequence; physiologic stressor; polymerase chain reaction; proopiomelanocortin; radioimmunoassay; reproductive development; time resolved data

DESCRIPTION: (Provided By Applicant) The hypothalamus-pituitary-adrenal (interrenal) axis HPA(l)J is a neuroendocrine network responsible for modulating a broad range of physiological functions from reproductive activity to chronic stress response. Within this network, corticotropic cells in the anterior lobe of the pituitary express proopiomelanocortin (POMC), a precursor protein from which the polypeptide hormone, adrenocorticotropin (ACTH), is post-translationally released. ACTH is well established as a critical link in this network. Neurons in the hypothalamus secrete corticotropin releasing hormone (CRH), which induces the secretion of ACTH from the anterior pituitary. ACTH, in turn, stimulates the adrenal gland to synthesize and release cortisol, which is the final hormone in the chronic stress response cascade. Fluctuations in the production and/or regulation of CRF, ACTH or cortisol can have serious consequences with respect to the survival of an organism. Hyposecretion of cortisol results in Addison's Disease. Conversely, hypersecretion of cortisol is associated with Cushing's Syndrome, a multi-symptom metabolic disorder characterized by muscle atrophy, immune deficiency, adrenal hyperplasia, kidney dysfunction and general tissue degeneration. In contrast to humans, where the U.S. frequency of Cushing's Syndrome is on the order of 3700 cases annually, 100 percent of Pacific salmon display Cushing's Syndrome-like tissue and organ degeneration coincident with spawning. While it had been thought that the stress of marine to freshwater migration was responsible for the post-spawning demise of these fish, studies have now implicated overproduction of cortisol during sexual maturation as the factor which ultimately leads to the demise of spawning salmon. The current proposal will use a combination of cell and molecular strategies to investigate the role of P0MG and hypothalamic neuropeptides (CRH, AVT and Uro I) in the regulation of the HPA axis. This wilt help to identify specific components of HPA(I) axis which are altered during the sexual maturation of Pacific salmon, and which lead to their inevitable post-spawning demise. An understanding of the molecular mechanisms underlying the development of Cushing's Syndrome-like pathology in Pacific Salmonids has the potential not only to advance our knowledge of the role of the HPA(I) in reproductive stress, but to contribute to a broader understanding of the etiology and pathogenesis of hypercorticism in humans.

描述：（由申请人提供）下丘脑-垂体-肾上腺 （肾间）轴 HPA(l)J 是一个神经内分泌网络，负责 通过生殖活动调节广泛的生理功能 对慢性应激反应。在这个网络中，促肾上腺皮质细胞 垂体前叶表达阿黑皮质素原 (POMC)，一种前体 多肽激素促肾上腺皮质激素 (ACTH) 的蛋白质 翻译后释放。 ACTH 是公认的关键环节 这个网络。下丘脑的神经元分泌促肾上腺皮质激素 激素（CRH），诱导垂体前叶分泌 ACTH。 ACTH 反过来刺激肾上腺合成和释放皮质醇， 这是慢性应激反应级联中的最后一种激素。波动 在 CRF、ACTH 或皮质醇的产生和/或调节中可能会产生严重的影响 对有机体生存的影响。分泌不足 皮质醇会导致艾迪生氏病。相反，皮质醇分泌过多 与库欣综合征（一种多症状代谢紊乱）有关 特点是肌肉萎缩、免疫缺陷、肾上腺增生、肾脏 功能障碍和一般组织退化。 与人类相比，美国库欣综合症的发病率位于 每年订购 3700 箱，100% 太平洋鲑鱼展示库欣鲑鱼 综合症样组织和器官退化与产卵同时发生。虽然它 人们认为海洋向淡水迁移的压力是 造成这些鱼产卵后死亡的原因，现在的研究已经发现 性成熟过程中皮质醇的过量产生是一个因素 最终导致产卵鲑鱼的死亡。 目前的提案将结合细胞和分子策略来 研究 P0MG 和下丘脑神经肽（CRH、AVT 和 Uro）的作用 I）HPA轴的调节。这将有助于识别特定的 HPA(I)轴的组成部分在性成熟过程中发生改变 太平洋鲑鱼，这导致它们产卵后不可避免的死亡。一个 了解发展的分子机制 太平洋鲑鱼中类似库欣综合征的病理学有可能不 只是为了增进我们对 HPA(I) 在生殖应激中的作用的了解， 但有助于更广泛地了解病因和发病机制 人类皮质亢进症。

项目成果

Seasonal changes in CRF-I and urotensin I transcript levels in masu salmon: correlation with cortisol secretion during spawning.

马苏鲑鱼 CRF-I 和尾加压素 I 转录水平的季节性变化：与产卵期间皮质醇分泌的相关性。

• DOI: 10.1016/j.ygcen.2007.03.013
• 发表时间: 2008
• 期刊: General and comparative endocrinology
• 影响因子: 2.7
• 作者: Westring,ChristianG;Ando,Hironori;Kitahashi,Takashi;Bhandari,RamjiKumar;Ueda,Hiroshi;Urano,Akihisa;Dores,RobertM;Sher,AnnaA;Danielson,PhillipB
• 通讯作者: Danielson,PhillipB