Regulation of the Gli protein TRA-1 by co-factors

辅因子对 Gli 蛋白 TRA-1 的调节

• 批准号: 9237835
• 负责人: RONALD E ELLIS
• 金额: $ 30.59万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237835
• 关键词: Activator Appliances; Adult; Affect; Anatomy; Animals; Anthelmintics; Binding Proteins; Biological Assay; Caenorhabditis; Caenorhabditis elegans; Cell Fate Control; Chromatin; Chromatin Structure; Cleaved cell; Complex; DNA; Development; Developmental Biology; Drosophila genus; Epigenetic Process; Equilibrium; Factor Analysis; Fertility; Fogs; Future; GLI Family Protein; Gene Targeting; Genes; Genetic Epistasis; Genetic Transcription; Genetic screening method; Germ Lines; Human; Human Development; Lead; Learning; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Measures; Missense Mutation; Modeling; Modification; Molecular Genetics; Mutation; Nematoda; Orthologous Gene; Output; Parasitic nematode; Pathway interactions; Phenotype; Play; Positioning Attribute; Process; Protein Isoforms; Proteins; RNA Interference; Regulation; Rest; Role; Spermatogenesis; System; Textbooks; Tissues; Transcriptional Regulation; Work; c new; developmental disease; experimental study; hedgehog signal transduction; human disease; mutant; nematode genetics; novel; prevent; promoter; sex determination; smoothened signaling pathway; transcription factor

Gli proteins constitute a vital but complex group of transcription factors. Humans have three, and mutations in them or errors in their regulation can cause developmental disorders or cancer. Our understanding of these proteins has rested on studies of their Drosophila ortholog Cubitus interruptus, which revealed that Gli proteins are a major target of the Hedgehog-signaling pathway, and can be processed to produce either activators or repressors. However, key questions about Gli function remain unanswered. In particular, it is not clear how much of their activity is controlled by co-factors, or what role they play in epigenetic changes. Since Gli proteins are broad transcriptional regulators, these questions are critical. Caenorhabditis nematodes provide an ideal model for answering these questions. They have a single Gli protein, TRA-1, that shares many similarities with human Gli proteins. However, TRA-1 controls sexual fates and plays a central role in self-fertility. As a result, the balance between its activating and repressing functions in the germ line makes C. briggsae ideal for identifying and evaluating co-factors. Finally, the anatomy of C. briggsae and C. elegans are simple and completely defined, which makes it feasible to study tissue-specific effects of chromatin regulation during development. Similar studies are difficult in other animals. The power of nematode genetics and developmental biology will simply the identification of Gli co-factors, and the analysis of how they work with TRA-1 to activate or repress targets. Indeed, direct transcriptional control and epigenetic effects can both be studied in living animals. Thus, this proposal has three aims: Aim #1: Define TRA-1 activator and repressor functions in Caenorhabditis nematodes. Aim #2: Determine how known co-factors interact with TRA-1 isoforms to regulate target genes. Aim #3: Identify new TRA-1 co-factors. Since TRA-1 is a model Gli protein, many of its co-factors and regulatory interactions are likely to be conserved. Thus, identifying co-factors and elucidating how they work with TRA-1 should illuminate human development and disease. In addition, novel co-factors that are not shared with humans could define new targets for antihelminthic drugs. Since preventing adult worms from reproducing in their human hosts is a critical for managing parasitic nematodes, the ability to target this part of the sex determination pathway could be invaluable. Finally, nematodes are one of the top models for sex determination (as shown by coverage in textbooks like Developmental Biology), so it is critical that we decipher the central part of the story.

GLI蛋白构成了一个至关重要但复杂的转录因子组。人类有三个，其中突变或调节中的错误会导致发育障碍或癌症。我们对这些蛋白质的理解已取决于对果蝇直系同源物的研究，这表明Gli蛋白是刺猬信号途径的主要目标，并且可以处理以产生激活剂或阻遏物。但是，有关GLI功能的关键问题仍未得到解决。特别是，尚不清楚他们的活动中有多少由共同因素控制，或者它们在表观遗传变化中的作用。由于GLI蛋白是广泛的转录调节剂，因此这些问题至关重要。 caenorhabditis nematodes为回答这些问题提供了理想的模型。它们具有单个Gli蛋白Tra-1，该蛋白与人Gli蛋白具有许多相似之处。但是，Tra-1控制着性命运，并在自育中起着核心作用。结果，其激活和抑制功能之间的平衡使得briggsae c. briggsae是识别和评估共同因素的理想选择。最后，briggsae和秀丽隐杆线虫的解剖结构是简单且完全定义的，这使得研究在发育过程中调节染色质的组织特异性作用是可行的。其他动物很难进行类似的研究。 线虫遗传学和发育生物学的力量将简单地识别GLI辅助因子，并分析它们与Tra-1的工作方式激活或抑制靶标。实际上，可以在活的动物中研究直接的转录控制和表观遗传效应。因此，该提议具有三个目标： AIM＃1：定义caenorhabditis炎线虫中的Tra-1激活剂和阻遏物功能。 AIM＃2：确定已知的辅助因子如何与Tra-1同工型相互作用以调节靶基因。 目标＃3：确定新的Tra-1共同因素。 由于TRA-1是一种模型Gli蛋白，因此其许多共同因素和调节相互作用可能是可以保存的。因此，确定共同因素并阐明它们如何与TRA-1一起工作应照亮人类的发展和疾病。此外，与人类没有共享的新型共同因素可以定义抗固有药物的新靶标。由于防止成年蠕虫在人类宿主中繁殖对于管理寄生线虫是至关重要的，因此针对这一部分性别确定途径的能力是无价的。最后，线虫是性别确定的主要模型之一（如发育生物学等教科书中所示），因此我们对故事的中心部分破译至关重要。