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 （igf）的重要性，特别是在胎儿期，当局部igf产生占主导地位时。出生后，肝脏成为IGFs合成最重要的部位，导致大量血浆库的形成。这种储存库依赖于出生后酸不稳定亚基（ALS）的产生，ALS是一种在长寿命三元复合物中招募IGF和IGF结合蛋白-3的蛋白质。直到我们发现ALS和血浆igf - 1储存库是出生后早期生长和骨骼发育所必需的，这个储存库的意义才被确定。现在我们将把这些研究扩展到正常和患病的后期产后生活状态。这与营养不良和分解代谢疾病有关，在这些疾病中，血浆igf - 1的降低与瘦质量的侵蚀有关。尽管存在这种关联，但基于igf - i的疗法取得了有限的成功，这反映出需要将其结合到三元复合物中才能有效。将追求三个具体目标，以解决ALS的作用和循环IGFs库在患病状态。目的A: igf - 1是骨骼肌质量的有效正调节因子。无ALS小鼠将受到已知可诱导血浆igf - 1变化和骨骼肌质量改变的挑战（即生长激素突然增加、营养缺乏或败血症）。目的B：人类血浆中IGF-II的含量是IGF-I的3倍。相反，小鼠的IGF-II很少，ALS小鼠的碳水化合物稳态正常。为了确定ALS在抑制IGF-II代谢作用中的作用，我们将研究过表达人IGF-II的无ALS小鼠。AIM C: GH通过增加转录刺激ALS合成。在体外，这种作用是由STAT5传递的，但这种机制的重要性仍有待在体内建立。利用STAT5缺失小鼠和肝细胞，我们将评估GH对ALS合成影响的直接和间接机制的贡献。研究GH对ALS转录的调控将为分解代谢疾病中肝脏GH抵抗的机制提供线索。总的来说，这些研究将显著促进我们对ALS和循环IGF库在产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.