MOLECULAR REGULATION OF IGF BINDING PROTEIN 1

性状：（改编自申请人摘要）胰岛素样生长因子 结合蛋白-1（IGFBP-1）是30 kDa的肝蛋白。是少校 IGF生物利用度和IGFBP-1循环水平短期调节剂 在多种临床疾病中升高， 包括控制不佳的糖尿病、肾衰竭、艾滋病 综合征与人类衰老胰岛素快速抑制肝脏产生 IGFBP-1通过胰岛素应答序列在基因转录水平上的表达 在IGFBP-1启动子的近端有一个IRSs。调查员报告说 通过蛋白激酶B（PKB）和前额蛋白的信号传导， 在胰岛素调节IGFBP-1基因表达中起关键作用。最近的研究 表明胰岛素对IGFBP-1启动子作用机制 活性在进化上是保守的，这表明它们在 介导相关生长因子对细胞存活的影响。IGFBP1 提供了一个重要的模型， 肝脏中胰岛素调节基因表达的介导作用机制， 以及相关生长因子对其他基本细胞过程的影响 包括细胞存活。拟议的研究将使用重组技术 和细胞培养模型，以检查这些特定的机制， 转录因子可能有助于多激素调节， IGFBP-1启动子活性。细胞培养和动物模型的研究将 确定这些机制是否在介导 胰岛素对肝脏内源性基因表达的影响。这些研究一起 将提供新的洞察的作用，信号，通过PKB和叉头 蛋白质，在介导胰岛素对基因表达的影响中起作用， 肝脏，专注于IGFBP-1的调节。

DESCRIPTION: (Adapted from the applicant's abstract) Insulin-like growth factor binding protein-1 (IGFBP-1) is a 30 kDa hepatic protein. It is the major short-term modulator of IGF bioavailability and circulating levels of IGFBP-1 are elevated in a variety of clinical disorders where anabolism is impaired, including poorly controlled diabetes mellitus, renal failure, the AIDS wasting syndrome and human aging. Insulin rapidly suppresses hepatic production of IGFBP-1 at the level of gene transcription via insulin response sequences (IRSs) located in the proximal IGFBP-1 promoter. The investigator has reported that signaling, via protein kinase B (PKB) and forehead proteins, plays a critical role in regulating IGFBP-1 gene expression by insulin. Recent studies indicate that mechanisms mediating the effect of insulin on IGFBP-1 promoter activity are evolutionarily conserved suggesting that they are important in mediating effects of related growth factors on cell survival. Hence, IGFBP1 provides an important model for understanding evolutionarily conserved mechanisms mediating effects of insulin-regulated gene expression in the liver, and the effects of related growth factors on other basic cell processes including cell survival. The proposed studies will use recombinant technologies and cell culture models to examine specific mechanisms by which these transcription factors may contribute to the multi-hormonal regulation of IGFBP-1 promoter activity. Studies in cell culture and animal models will determine whether these mechanisms play a critical role in mediating effects of insulin on endogenous gene expression in the liver. Together, these studies will provide new insight into the role that signaling, via PKB and forkhead proteins, plays in mediating effects of insulin on gene expression in the liver, focusing on the regulation of IGFBP-1.