HOMEOPROTEIN AND NEUROENDOCRINE PHENOTYPE

同源蛋白和神经内分泌表型

• 批准号: 2703041
• 负责人: Elaine J. Lewis
• 金额: $ 19.14万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 1999-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2703041
• 关键词: catecholamines; developmental genetics; developmental neurobiology; dopamine beta monooxygenase; enzyme induction /repression; hormone biosynthesis; laboratory mouse; laboratory rat; neuroendocrine system; neurotransmitter biosynthesis; norepinephrine; nucleic acid sequence; oligonucleotides; phenotype; transcription factor

DESCRIPTION: One of the key events defining the specificity of cell function in neuroendocrine tissues is the identity of neurotransmitter expressed in a given cell. The molecular events that control the selection of neurotransmitter phenotype are influenced by environmental stimuli. Ultimately, cellular phenotype is determined by the interaction of functionally distinct transcription factors with regulatory elements of genes that encode neurotransmitters or neurotransmitter biosynthetic enzymes. This application is focused on characterizing a transcription factor that interacts with the regulatory region of the dopamine b hydroxylase (DBH) gene. DBH catalyzes the synthesis of norepinephrine, and is expressed only in sympathetic neurons, adrenal chromaffin cells and certain brain nuclei. The applicant has cloned a cDNA for this transcription factor, designated Arix, which carries a homeobox, and has found that Arix mRNA is selectively expressed in noradrenergic tissues and cell lines. These observations suggest that Arix may play a definitive role in the determination of the noradrenergic phenotype in vivo. The main objective of this proposal is to understand the potential role of Arix in regulating the noradrenergic phenotype. This goal will be achieved by: (1) defining the pattern of Arix expression in the rat peripheral and central nervous system during embryonic and postnatal development; (2) identifying the molecular components of Arix-containing DNA-protein complexes, and (3) inactivating Arix activity in a catecholaminergic cell line. The results of these studies should lead to further understanding of the normal development of the sympathoadrenal phenotype, as well as the consequences of a failure of development to proceed. In addition, the Arix gene may prove to be a factor in inherited diseases characterized by the aberrant development of neuroendocrine cells.

描述：定义细胞特异性的关键事件之一 神经内分泌组织的功能是神经递质的身份 在给定的单元格中表达。控制分子事件 神经递质表型的选择受环境影响 刺激。最终，细胞表型由相互作用决定 具有调节元件的功能不同的转录因子 编码神经递质或神经递质生物合成的基因 酶。该应用程序的重点是表征转录 与多巴胺 b 调节区相互作用的因子 羟化酶（DBH）基因。 DBH 催化去甲肾上腺素的合成， 仅在交感神经元、肾上腺嗜铬细胞中表达 和某些脑核。申请人已为此克隆了cDNA 转录因子，命名为 Arix，携带同源盒，并且具有 发现 Arix mRNA 在去甲肾上腺素能组织中选择性表达 和细胞系。这些观察结果表明 Arix 可能会扮演 在去甲肾上腺素能表型的测定中起决定性作用 体内。该提案的主要目的是了解潜在的 Arix 在调节去甲肾上腺素能表型中的作用。这个目标将 通过以下方式实现： (1) 定义大鼠中 Arix 表达的模式 胚胎和出生后的周围和中枢神经系统 发展; (2) 鉴定Arix含分子成分 DNA-蛋白质复合物，以及 (3) 灭活 Arix 活性 儿茶酚胺能细胞系。这些研究的结果应该导致 进一步了解交感肾上腺的正常发育 表型，以及发育失败的后果 继续。 此外，Arix 基因可能被证明是一个因素 以异常发育为特征的遗传性疾病 神经内分泌细胞。