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

激素在动物体内引起多重作用的方法仍然是化学信号传导领域的一个核心问题。例如，已知生长激素（GH）调节多种过程，包括生长、代谢、繁殖、渗透调节、免疫功能和行为等方面，但这些不同过程背后的机制尚未完全了解。在这个项目中，虹鳟鱼将被用作模型生物来评估生长激素的两种不同作用：1)促进生长，一个合成代谢过程；2)分解和动员储存的脂肪储备（脂肪分解），一个分解代谢过程。像鳟鱼这样的鱼类为研究这个问题提供了一个合适的系统，因为它们一生都在生长（不确定生长），并表现出不同的脂质储存策略，导致重要的生长促进[即胰岛素样生长因子-1 （IGF-1）的合成和分泌]和脂质储存/脂质分解过程在相同的细胞类型（例如肝细胞，主要的脂质储存以及IGF-1合成的主要部位）中共定位。这项为期四年的工作计划将综合几种方法（例如，生理、细胞、生化/分子/基因组），并分三个阶段解决这个问题。在第一阶段，我们将表征GH受体（GHR）的结合特性，并评估其对与GH结构相似的不同激素（如催乳素）的选择性。在第二阶段，我们将确定生长激素激活的细胞信号通路，以及这些通路如何通过合成代谢到分解代谢的转变而重新编程。这将建立ghr效应通路的联系。在第三阶段，我们将阐明信号通路与特定生物反应之间的联系，并具体评估生长促进（例如，IGF-1的产生）和脂肪分解的差异激活。该项目将从根本上推进我们对生长和代谢协调的理解，首次阐明细胞通过重编程来抑制生长激素促进生长的作用，从而使其具有溶脂作用。此外，该项目将提供关于生长激素刺激脂肪分解（通过激素敏感脂肪酶激活和/或合成）机制的新信息，以及关于ghr和ghr效应系统联系的调节。虽然这项工作只涉及鱼类，但它对理解脊椎动物生长-代谢相互作用的本质和进化具有广泛的意义。这个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，使美国的科学事业多样化。它还将为研究生和本科生提供研究教育和培训机会，包括代表性不足的群体的成员。该项目将特别通过课程开发、研讨会和夏令营吸引该州部落学院的教师和学生。这些活动将导致部落学院以学生为中心的合作研究项目。研究结果还将应用于提高鱼类、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.