REGULATION OF THE HEPATIC NEGATIVE ACUTE PHASE RESPONSE

描述（改编自应用程序） Denson博士将把他的大部分时间用于临床导向的基础 research.该奖项将提供受保护的研究时间，额外的 教学培训和购买试剂。它将支持追求 直接的研究目标，以及建立一个独立的 实验室儿科部门保证丹森医生80%的 今后五年的时间将用于研究活动。的 肝细胞对细胞因子的反应包括减少关键的 代谢蛋白质;这构成负急性期反应（APR）。 不良临床后果包括线性生长、肝细胞损伤 运输，葡萄糖和药物代谢，由于下调 调节基因本提案的主要目的是确定 细胞因子抑制表达的细胞质信号传导机制 临床上重要的肝脏基因，包括生长激素受体和 白蛋白。我们之前的研究已经证明了肝细胞的抑制 转运蛋白和白蛋白启动子通过肿瘤坏死驱动荧光素酶活性 因子α（TNF-α）或白细胞介素-1 β（IL-1B）。类维生素A反应元件 已显示可介导肝细胞转运蛋白的协同还原 IL-1B和神经酰胺的表达。AIM I的目标是确定 细胞因子应答元件和相关的转录因子， HepG 2细胞和原代大鼠生长激素受体和白蛋白的表达 肝细胞AIM 2的目标是表征细胞质信号 介导这些反式激活因子的细胞因子抑制的转导机制 和相关的靶基因。初步研究将确定神经酰胺的作用 这些基因的急性期下调信号。AIM 3的目标是 是为了证实细胞因子信号通路的重要性， 目的I和2为体内急性期基因调控。野生型和IL-1B以及 将用内毒素处理TNF-α受体缺陷小鼠，并观察其对TNF-α受体的影响。 胞质信号蛋白和靶向调节反式激活因子和基因 将被确定。阐明这些分子机制将有助于 为了更广泛地理解，几个重要的监管之间的联系 肝脏代谢途径在健康和疾病，并可能最终导致 更具体地治疗马槟榔引起的炎性并发症 疾病，如线性生长障碍。

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.