Resolving the growth-promoting and lipid catabolic actions of growth hormone

激素在动物体内引发多重效应的方式仍然是化学信号领域的一个中心问题。例如，已知生长激素（GH）调节几个过程，包括生长、代谢、生殖、免疫调节、免疫功能和行为的各个方面，但这些不同过程的机制尚未完全理解。在这个项目中，虹鳟鱼将被用作模式生物，以评估GH的两个不同的行动：1）生长促进，合成代谢过程，和2）分解和动员储存的脂质储备（脂解），分解代谢过程。鱼类如鳟鱼提供了一个合适的系统来研究这个问题，因为它们在整个生命周期中生长（不确定的生长），并显示出多样化的脂质储存策略，导致重要的促生长因子（即，胰岛素样生长因子-1（IGF-1）合成和分泌]和相同细胞类型内的脂质储存/脂解过程（例如，肝细胞，主要的脂质储存以及IGF-1合成的主要位点）。四年期工作计划将纳入若干办法（例如，生理学、细胞学、生物化学/分子学/基因组学），并分三个阶段解决问题。在第一阶段，我们将表征GH受体（GHR）结合特性，并评估其对结构上与GH相似的不同激素的选择性（例如，催乳素）。在第2阶段，我们将确定GH激活的细胞信号通路，以及这些通路如何通过合成代谢向分解代谢转变而重新编程。这将建立GHR-效应子途径联系。在第3阶段，我们将阐明信号通路和特定生物反应之间的联系，并特别评估生长促进的差异激活（例如，IGF-1产生）和脂肪分解。该项目将从根本上推进我们对生长和代谢协调的理解，首次阐明了细胞重新编程以抑制GH的促生长作用以使其脂解作用的方法。此外，该项目还将提供有关GH刺激脂解（通过对脂肪酶敏感的脂肪酶激活和/或合成）的机制以及GHR和GHR效应子系统连接的调节的新信息。虽然这项工作专门涉及鱼类，但它将对理解脊椎动物生长-代谢相互作用的性质和演变具有广泛的相关性。该项目将产生许多其他广泛的影响。它将扩大北达科他州的关键研究基础设施，这有助于使国家的科学事业多样化。它还将为研究生和本科生，包括代表性不足的群体的成员提供研究教育和培训机会。该项目将通过课程开发、研讨会和夏令营，专门吸引该州部落学院的教师和学生。这些活动，将导致一个合作的学生为中心的研究项目在部落学院。这些发现还将用于提高鱼类、家禽和家畜的农业生产，以及检测和治疗动物和人类的各种生长/代谢紊乱。

The means by which hormones elicit multiple effects in animals remains a central question in the field of chemical signalling. For example, growth hormone (GH) is known to regulate several processes, including aspects of growth, metabolism, reproduction, osmoregulation, immune function, and behaviour, yet the mechanisms that underlie these diverse processes are not fully understood. In this project, rainbow trout will be used as a model organism to evaluate two disparate actions of GH: 1) growth promotion, an anabolic process, and 2) breakdown and mobilization of stored lipid reserves (lipolysis), a catabolic process. Fish such as trout provide an opportune system in which to examine this problem because they grow throughout their life (indeterminate growth) and display a diverse lipid storage strategy that results in the colocalization of important growth-promoting [i.e., insulin-like growth factor-1 (IGF-1) synthesis and secretion] and lipid storage/lipolysis processes within the same cell types (e.g., liver cells, a main lipid store as well as the principal site of IGF-1 synthesis). The 4-year plan of work will integrate several approaches (e.g., physiological, cellular, biochemical/molecular/ genomic) and address the problem in three phases. In the first phase, we will characterize GH receptor (GHR) binding properties and assess its selectivity for different hormones that are structurally similar to GH (e.g., prolactin). In phase 2, we will identify the cell signal pathways activated by GH and how these pathways are reprogrammed by an anabolic to catabolic shift. This will establish GHR-effector pathway linkages. In phase 3, we will elucidate linkages between signal pathways and specific biological responses, and specifically evaluate differential activation of growth-promotion (e.g., IGF-1 production) and lipolysis. This project will fundamentally advance our understanding of the coordination of growth and metabolism by elucidating for the first time the means by which cells get reprogrammed to repress the growth-promoting actions of GH to enable its lipolytic actions. In addition, this project will provide novel information about the mechanisms by which GH stimulates lipolysis (via hormone-sensitive lipase activation and/or synthesis) and about the regulation of GHRs and GHR-effector system linkages. While this work pertains specifically to fish, it will have broad relevance to understanding the nature and evolution of growth-metabolism interactions in vertebrates generally. This project will have numerous other broad impacts. It will expand critical research infrastructure in North Dakota, which serves to diversify the nation's scientific enterprise. It also will afford research education and training opportunities to graduate and undergraduate students, including members of underrepresented groups. The project will specifically engage faculty and students of the state's tribal colleges through curriculum development, workshops, and summer camps. These activities that will lead to a collaborative student-centered research project at a tribal college. The findings also will have application to enhancing agricultural production of fish, poultry, and domestic livestock, as well as to the detection and treatment of various growth/metabolic disorders in animals and humans.