Developmental Regulation of Neuropeptide Expression

神经肽表达的发育调节

• 批准号: 7149987
• 负责人: Paul H Taghert
• 金额: $ 33.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149987
• 关键词: Address; BHLH Protein; Basic Science; Biological Assay; Biology; Brain; Cell Differentiation process; Cells; Code; Collaborations; Data; Development; Disease; Drosophila genus; Elements; Embryo; Enzymes; Facility Construction Funding Category; Future; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Grant; Homeodomain Proteins; Human; In Vitro; Lead; Light; Methods; Molecular Genetics; Neuroendocrine Cell; Neurons; Neuropeptides; Neurosecretory Systems; Pan Genus; Pancreas; Peptides; Phase; Phenotype; Pituitary Gland; Proteins; Regulation; Research; Stem cells; Stress; Syndrome; Transfection; Work; base; brain cell; cell type; design; in vivo; peptide hormone; programs; research study; transcription factor; tumor

DESCRIPTION (provided by applicant): The brain's proper functioning depends on the establishment of diverse cellular phenotypes. Our research program addresses the mechanisms that regulate differentiation of neuroendocrine cells during development. We use Drosophila molecular genetics to examine the biology of a basic HLH protein called Dimmed. Our genetic studies indicate DIMM promotes neuroendocrine differentiation in two ways. First it supports specific cell fate decisions (e.g., specific peptide hormone expression) in collaboration with other factors. Additionally, DIMM individually and strongly regulates at least one common neuroendocrine gene (encoding a peptide biosynthetic enzyme called PHM): DIMM expression is normally coincident with PHM, and when DIMM is mis-expressed it confers a PHM phenotype onto most or all brain cells. DIMM is related to the mammalian protein Mist1, a factor also implicated in neuroendocrine differentiation. We hypothesize that DIMM is a dedicated, pro-secretory regulatory factor with conserved functions, whose study will lead to a better understanding of the organization and differentiation of neuroendocrine cell types. This basic research program will support efforts to address human syndromes caused by underlying neuroendocrine disorders, such as stress, or tumor formation in the pituitary or pancreas, and will help guide future programs of stem cell differentiation to generate specific neuroendocrine lineages in vitro. To pursue this research program, we propose three specific aims. First we will examine the mechanisms by which DIMM collaborates with other factors to promote specific peptide hormone expression by subsets of neuroendocrine cells. Second we will examine mechanisms by which DIMM promotes a common program of differentiation for all neuroendocrine cells. We hypothesize that program represents expression of a core set of genes, one of which we have identified as PHM. Because dimm expression predicts and defines subsequent neuroendocrine differentiation, the factors working upstream of dimm are significant. Therefore, the third aim plans genetic screens to identify factors that regulate dimm expression.

描述（由申请人提供）：大脑的正常功能取决于建立各种细胞表型。我们的研究计划解决了调节开发过程中神经内分泌细胞分化的机制。我们使用果蝇分子遗传学来检查一种称为DIMMED的碱性HLH蛋白的生物学。我们的遗传研究表明DIMM通过两种方式促进了神经内分泌的分化。首先，它支持特定的细胞命运决策（例如，特定的肽激素表达）与其他因素合作。此外，DIMM单独和强烈调节了至少一个常见的神经内分泌基因（编码称为PHM的肽生物合成酶）：DIMM表达通常与PHM一致，当DIMM表达错误时，它将PHM表现为大多数或所有脑细胞。 DIMM与哺乳动物蛋白雾有关，这也与神经内分泌分化有关。我们假设DIMM是具有保守功能的专用，促递减的调节因素，其研究将使对神经内分泌细胞类型的组织和分化有更好的了解。这项基础研究计划将支持解决由垂体或胰腺中诸如压力或肿瘤形成之类神经内分泌疾病引起的人类综合症的努力，并将帮助指导未来的干细胞分化程序以在体外生成特定的神经内分泌谱系。 为了遵循该研究计划，我们提出了三个具体目标。首先，我们将研究DIMM与其他因素合作的机制，以通过神经内分泌细胞的亚群促进特定的肽激素表达。其次，我们将研究DIMM促进所有神经内分泌细胞的共同分化程序的机制。我们假设该程序代表了一组核心基因的表达，我们已将其确定为PHM。由于DIMM表达预测并定义了随后的神经内分泌分化，因此DIMM上游的因素很重要。因此，第三个目标计划遗传筛选以识别调节DIMM表达的因素。