REGULATION OF THE HEPATIC NEGATIVE ACUTE PHASE RESPONSE

说明(改编自应用程序) Denson博士将把他的大部分时间花在面向临床的基础上 研究。这项奖励将规定受保护的研究时间，另外 授课培训，以及购买试剂。它将支持对 近期的研究目标，以及建立独立的 实验室。儿科部门已经保证，80%的丹森医生的 未来五年的时间将专门用于研究活动。这个 肝细胞对细胞因子的反应包括Key合成减少 代谢蛋白；这构成了负急性时相反应(APR)。 不良的临床后果包括线性生长障碍，肝细胞 转运，葡萄糖和药物代谢，由于下调 调控基因。这项提案的主要目标将是确定 细胞因子抑制血管内皮生长因子表达的细胞质信号机制 临床上重要的肝脏基因，包括生长激素受体和 白蛋白。我们先前的研究表明，抑制肝细胞 转运蛋白和白蛋白启动子驱动的肿瘤坏死荧光素酶活性 因子α(TNF-a)或白介素1β(IL-1B)。类维甲酸反应元件 已被证明可以调节肝细胞转运蛋白的协调减少 IL-1B和神经酰胺的表达。AIM I的目标将是确定 调节细胞因子反应元件和相关转录因子 生长激素受体和白蛋白在HepG2细胞和原代大鼠体内的表达 肝细胞。AIM 2的目标将是表征细胞质信号 介导细胞因子抑制这些反式激活因子的转导机制 以及相关的靶基因。初步研究将确定神经酰胺的作用 信号在急性期下调这些基因的表达。AIM 3的目标是 确认细胞因子信号转导通路的重要性 目的1和2对体内急性期基因调控。野生型和IL-1B及 内毒素对肿瘤坏死因子-a受体缺陷小鼠的治疗作用 胞质信号蛋白与靶调控反式激活因子和基因 将会被确定。阐明这些分子机制将有助于 为了更广泛地理解，几个重要的监管联系 健康和疾病中的肝脏代谢途径，并可能最终导致 对细胞因子引起的炎性并发症进行更具体的治疗 直线生长失灵等疾病。

DESCRIPTION (adapted from the application) Dr. Denson will devote the majority of his time to clinically-oriented basic research. This award will provide for protected time for research, additional didactic training, and the purchase of reagents. It will support pursuit of the immediate research aims, as well as the establishment of an independent laboratory. The Department of Pediatrics has assured that 80% of Dr. Denson's time over the next five years will be dedicated to research activities. The hepatocyte's response to cytokines includes a reduction in the synthesis of key metabolic proteins; this constitutes the negative acute phase response (APR). Adverse clinical consequences include impairments of linear growth, hepatocyte transport, and glucose and drug metabolism, due to down-regulation of regulatory genes. The primary objective of this proposal will be to determine the cytoplasmic signaling mechanisms by which cytokines suppress expression of clinically important hepatic genes, including the growth hormone receptor and albumin. Our prior studies have demonstrated suppression of hepatocyte transporter and albumin promoter-driven luciferase activity by tumor necrosis factor alpha (TNF-a) or interleukin-1 Beta (IL-1B). Retinoid response elements have been shown to mediate coordinate reduction of hepatocyte transporter expression by IL-1B and ceramide. The goal of AIM I will be to identify cytokine response elements and associated transcription factors which regulate growth hormone receptor and albumin expression in HepG2 cells and primary rat hepatocytes. The goal of AIM 2 will be to characterize the cytoplasmic signal transduction mechanisms mediating cytokine suppression of these transactivators and associated target genes. Initial studies will define the role of ceramide signaling in acute phase down-regulation of these genes. The goal of AIM 3 will be to confirm the significance of cytokine signaling pathways identified in Aims I and 2 to in vivo acute phase gene regulation. Wild type and IL-1B and TNF-a receptor deficient mice will be treated with endotoxin and effects upon cytoplasmic signaling proteins and target regulatory transactivators and genes will be determined. Clarification of these molecular mechanisms will contribute to a broader understanding, of the regulatory links between several important hepatic metabolic pathways in both health and disease, and may ultimately lead to more specific treatments for cytokine-induced complications of inflammatory diseases such as linear growth failure.