Regulation of ALS and Its Role in the IGF System

ALS 的调节及其在 IGF 系统中的作用

• 批准号: 6871221
• 负责人: YVES R BOISCLAIR
• 金额: $ 32.88万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-26 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871221
• 关键词: SDS polyacrylamide gel electrophoresis; binding proteins; biological models; biotransformation; developmental disease /disorder; genetic transcription; growth factor receptors; high performance liquid chromatography; hormone regulation /control mechanism; insulinlike growth factor; iron sulfur protein; laboratory mouse; plasmids; polymerase chain reaction; protein biosynthesis; protein structure function; proteolysis; spectrometry; striated muscles; transfection; western blottings

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.

描述（由申请人提供）：基因缺失研究已经证明了IGF-I和II（IGFs）的重要性，特别是在胎儿期，当局部IGFs产生占主导地位时。出生后，肝脏成为IGFs合成的最重要部位，导致大量血浆储库的发育。这个储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。这个储库的意义一直不确定，直到我们发现ALS和血浆IGF-I储库是出生后早期生长和骨发育所必需的。我们现在将这些研究扩展到产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，其中血浆IGF-I降低与瘦体重减少有关。尽管存在这种关联，但基于IGF-I的疗法取得的成功有限，这反映了将其纳入三元复合物以获得有效性的需要。将追求三个具体目标来解决ALS和循环IGFs库在疾病状态期间的作用。目的：IGF-I是一种有效的骨骼肌质量正调节剂。将MANAALS小鼠进行已知诱导血浆IGF-I变化和改变骨骼肌质量（即，GH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。相比之下，小鼠几乎没有IGF-II，而无ALS小鼠具有正常的碳水化合物稳态。为了确定ALS在抑制IGF-II代谢效应中的作用，我们将研究过表达人IGF-II的空型ALS小鼠。目的C：GH通过增加转录刺激ALS合成。在体外，这种作用是由STAT 5传递的，但这种机制的重要性仍有待于在体内建立。使用null STAT 5小鼠和肝细胞，我们将评估直接和间接机制介导的GH对ALS合成的影响的贡献。研究ALS转录的GH调节将为分解代谢疾病期间肝GH抵抗的发展机制提供线索。总的来说，这些研究将大大促进我们对ALS和循环IGF库在出生后疾病中所起作用的理解。