REGULATION OF EXPRESSION OF ACID BETA-GLUCOSIDASE

酸性 β-葡萄糖苷酶表达的调节

• 批准号: 2140495
• 负责人: FRANCES SMITH
• 金额: $ 13.06万
• 依托单位: EUNICE KENNEDY SHRIVER CTR MTL RETARDATN
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2140495
• 关键词: Gaucher's disease; beta glucosidases; biological models; developmental neurobiology; embryo /fetus; enzyme activity; gene expression; human subject; infant animal; laboratory mouse; leukocytes; messenger RNA; protein metabolism; transcription factor

A deficiency in acid beta-glucosidase (betaGlc) causes Gaucher disease, which ranges in severity from a neurologically devastating disease in infancy to a mild disease in adulthood. A thorough understanding of the mechanisms that control betaGlc expression is necessary to design future therapeutic interventions, particularly gene therapy. this proposal aims to elucidate the regulation of betaGlc expression, placing particular emphasis on neural cells and cells of the monocyte/macrophage lineage, which are adversely affected in Gaucher disease. Specifically, we will determine: (1) What mechanisms control basal levels of betaGlc activity in different tissues? We have shown already that betaGlc mRNA expression plays a major role in differential betaGlc expression. We now plan to determine the role of protein turnover in regulating betaGlc activity, and to elucidate the role of transcription and mRNA stability in controlling betaGlc mRNA levels. We also plan to identify the sequences that control betaGlc mRNA levels, and the proteins that bind these elements. Preliminary results indicate that the betaGlc promoter contains elements that are recognized by tissue specific and ubiquitous factors. (2) Does feedback regulation control betaGlc gene expression? BetaGlc activity in vivo increases in response to procedures that increase substrate level. We will establish an in vitro model in which the role of substrate accumulation on betaGlc expression can be evaluated. (3) How is betaGlc activity regulated in the developing nervous system? BetaGlc activity is high in mouse fetal brain and declines in the neonate. Using the mouse as a model system, betaGlc activity and mRNA levels will be measured during brain development. We will investigate how changes in the amounts of the transcription factors identified in aim #1 may influence betaGlc expression in vivo in the brain. Also, because it is possible that the developmental regulation of betaGlc may be driven by substrate levels, changes in the factors that control feedback regulation in neural cells elucidated in aim #2 also will be investigated. A detailed understanding of the control of betaGlc expression in neural cells has important implications not only for gene therapy of severe Gaucher disease, but also for the treatment of other neurological diseases that require gene expression in multiple cell types.

酸性β-葡糖苷酶（β Glc）的缺乏导致戈谢病， 其严重程度从神经系统破坏性疾病到 从婴儿期到成年期的轻微疾病。 的透彻理解 控制betaGlc表达的机制对于设计未来的 治疗干预，特别是基因治疗。 这项建议旨在 为了阐明betaGlc表达的调节，特别是 强调神经细胞和单核细胞/巨噬细胞谱系的细胞， 其在戈谢病中受到不利影响。 具体来说，我们将 确定：（1）什么机制控制betaGlc活性的基础水平 在不同的组织中？ 我们已经证明β-葡萄糖基化mRNA的表达 在β-Glc的差异表达中起主要作用。 我们现在计划 确定蛋白质周转在调节betaGlc活性中的作用， 并阐明转录和mRNA稳定性在 控制betaGlc mRNA水平。 我们还计划鉴定 控制betaGlc mRNA水平的蛋白质，以及结合这些蛋白质的蛋白质， 元素 初步结果表明betaGlc启动子 含有组织特异性和普遍存在的识别元素 因素 (2)反馈调节控制betaGlc基因表达吗？ 体内BetaGlc活性响应于 增加底物水平。 我们将建立一个体外模型， 底物积累对β Glc表达作用可以是 评估。 (3)在发展中如何调节betaGlc活性 神经系统？ BetaGlc活性在小鼠胎脑中高， 在新生儿中下降。 使用小鼠作为模型系统， 活性和mRNA水平将在大脑发育期间测量。 我们 将研究转录因子数量的变化 在目的#1中鉴定的β-Glc可能会影响体内β-Glc的表达。 个脑袋 同时，因为发育调节 β-Glc的变化可能受底物水平的影响， 目标2中还阐明了神经细胞的控制反馈调节 将进行调查。 详细了解betaGlc的控制 在神经细胞中的表达不仅对基因表达具有重要意义， 严重戈谢病的治疗，但也用于治疗其他 需要多细胞基因表达的神经系统疾病 类型