Astrocyte-specific expression of serpin genes

描述（由申请人提供）：α -l-抗凝乳胰蛋白酶（ACT）是一种丝氨酸蛋白酶抑制剂（serpin），特异性地与阿尔茨海默病患者大脑中的β -淀粉样蛋白沉积物共定位。ACT还增强了阿尔茨海默病双转基因小鼠模型中β -淀粉样蛋白沉积的形成。星形胶质细胞是大脑中发现的ACT的主要来源，在脑炎症过程中，这种serpin的表达增强。本研究旨在阐明ACT在人脑星形胶质细胞中的组织特异性表达及其在这些细胞中被IL-1和肿瘤坏死因子（TNF）上调的机制。编码ACT的基因位于染色体14q32.1的远端蛇形蛋白亚簇。位于该亚群的所有基因都在肝细胞中表达，但只有ACT基因在星形胶质细胞中转录。此外，肝细胞特异性转录因子在星形胶质细胞中不表达。基于我们的初步研究，我们假设这个远端亚簇的“星形胶质细胞特异性”染色质结构决定了serpin基因在大脑中的表达模式。然而，决定这种“星形胶质细胞特异性”结构的组织特异性转录因子尚不清楚，它们的鉴定对于充分了解ACT基因的组织特异性表达至关重要。为此，我们提出以下具体目标：

DESCRIPTION (provided by applicant): alpha-l-antichymotrypsin (ACT) is a serine proteinase inhibitor (serpin) that specifically co-localizes with beta-amyloid deposits in the brains of Alzheimer's patients. ACT also enhances the formation of beta-amyloid deposits in a double transgenic mouse model of Alzheimer's disease. Astrocytes are the major source of ACT found in the brain and expression of this serpin is enhanced during brain inflammatory processes. The goals of this research proposal have been designed to elucidate mechanisms of tissue-specific expression of ACT in human brain astrocytes and its up-regulation by IL-1 and tumor necrosis factor (TNF) in these cells. The gene encoding ACT is located in a distal serpin subcluster on chromosome 14q32.1. All genes located in this subcluster are expressed in hepatocytes but only the ACT gene is transcribed in astrocytes. In addition, hepatocyte-specific transcription factors are not expressed in astrocytes. Based on our preliminary studies we hypothesized that "astrocyte specific" chromatin structure of this distal subcluster determines the expression pattern of serpin genes in the brain. However, tissue-specific transcription factors that determine this "astrocyte specific" structure are not known and their identification is critical for a full understanding of the tissue-specific expression of the ACT gene. Therefore, we propose the following specific aims: 1) To compare the chromatin structure of the distal serpin subcluster in astrocytes to that in hepatocytes and tissue-specific microcell hybrids. 2) To identify the specific regulatory elements and transcription factors that are responsible for astrocyte-specific expression of the ACT gene. 3) To identify the mechanism of tissue-specific activation of the ACT gene by IL-1 and TNF.