Regulation of ALS and Its Role in the IGF System

描述(由申请人提供)：基因缺失研究已经证明了IGF-I和IGF-II(IGFS)的重要性，特别是在胎儿时期，当地IGFS的产生占主导地位。出生后，肝脏成为IGFS合成的最重要部位，导致大量血浆库的发育。这个储存库依赖于出生后酸性不稳定亚单位(ALS)的产生，ALS是一种在长寿命的三元复合体中招募IGFS和IGF结合蛋白-3的蛋白质。直到我们证明ALS和血浆IGF-I储存库是出生后早期生长和骨骼发育所必需的，这个储存库的意义一直不确定。我们现在将把这些研究扩展到出生后生活的正常和疾病状态。这与营养不良和分解代谢疾病有关，在这些疾病中，血浆IGF-I下降与瘦体重的侵蚀有关。尽管存在这种关联，但基于IGF-I的治疗取得的成功有限，反映出需要将它们合并到三元复合体中才能有效。将追求三个具体目标来解决ALS和疾病状态下循环的IGFS储存库的作用。目的：胰岛素样生长因子-I(IGF-I)是一种强有力的骨骼肌正向调节因子。ALS缺陷型小鼠将受到已知的诱导血浆IGF-I变化和改变骨骼肌质量的挑战(即生长激素突然增加、营养缺乏或脓毒症)。目的B：人类血浆IGF-II的含量是IGF-I的3倍。相比之下，小鼠的IGF-II很少，ALS缺陷型小鼠的碳水化合物平衡正常。为了确定肌萎缩侧索硬化症在抑制IGF-II代谢效应中的作用，我们将研究过表达人IGF-II的ALS小鼠。目的：C：GH通过提高转录水平刺激ALS合成。在体外，这一作用是由STAT5传递的，但这一机制的重要性仍有待在体内建立。利用Null STAT5小鼠和肝细胞，我们将评估直接和间接机制在GH对ALS合成影响中的作用。研究GH对ALS转录的调控将为了解分解代谢疾病时肝脏GH抵抗的发生机制提供线索。总体而言，这些研究将极大地促进我们对ALS和循环中的IGF储存库在出生后生活疾病中所起作用的理解。

DESCRIPTION (provided by applicant): Gene deletion studies have demonstrated the importance of IGF-I and II (IGFs), particularly during fetal life when local IGFs production predominates. After birth, the liver becomes the most important site of IGFs synthesis, resulting in the development of a substantial plasma reservoir. This reservoir is dependent on the postnatal production of the acid labile subunit (ALS), a protein that recruits IGFs and IGF Binding Protein-3 in long-lived ternary complexes. The significance of this reservoir has been uncertain until we showed that ALS and the plasma IGF-I reservoir are required for early postnatal growth and bone development. We now will extend these studies to normal and diseased states of later postnatal life. This is relevant to malnutrition and catabolic illnesses in which decreased plasma IGF-I is associated with erosion of lean mass. Despite this association, IGF-I-based therapies have had limited success, reflecting the need for their incorporation into ternary complexes for effectiveness. Three specific aims wilt be pursued to address the role of ALS and the circulating IGFs reservoir during diseased states. AIM A: IGF-I is a potent positive regulator of skeletal muscle mass. Null ALS mice will be subjected to challenges known to induce changes in plasma IGF-I and to alter the mass of skeletal muscles (i.e., sudden increase in GH, nutritional deficiency or sepsis). AIM B: Humans have 3 times as much plasma IGF-II than IGF-I. In contrast, mice have little IGF-II and null ALS mice have normal carbohydrate homeostasis. To determine the role of ALS in containing the metabolic effects of IGF-II, we will study null ALS mice over-expressing human IGF-II. AIM C: GH stimulates ALS synthesis by increasing transcription. In vitro, this effect is conveyed by STAT5, but the importance of this mechanism remains to be established in vivo. Using null STAT5 mice and liver cells, we will evaluate the contribution of direct and indirect mechanisms mediating the effects of GH on ALS synthesis. Studying the GH-regulation of ALS transcription will provide clues to mechanisms responsible for development of hepatic GH resistance during catabolic diseases. Overall, these studies will significantly advance our understanding of the roles played by ALS and the circulating IGF reservoir in diseases of postnatal life.