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Mutually Exclusive Odorant Receptor Regulation

互斥的气味受体调节

基本信息

批准号：
8656095
负责人：
Robert P. Lane
金额：
$ 34.13万
依托单位：
WESLEYAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8656095
关键词：
Address Afferent Neurons Alleles Applications Grants Beckwith-Wiedemann Syndrome Biological Cell Culture System Cell Differentiation process Cell Line Cell Separation Cell fusion Cells ChIP-on-chip Characteristics Chromatin Code Communities Complement Complex Confocal Microscopy DNA Data Data Set Development Device or Instrument Development Disease Elements Epigenetic Process Feedback Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genome Genotype Health Hereditary Disease Histone Code Histones In Situ Hybridization In Vitro Life Lysine Mammals Mediating Medical Messenger RNA Modeling Molecular Mus Natural regeneration Neurons Neurosciences Nuclear Nuclear RNA Odorant Receptors Olfactory Epithelium Oncogenic Organism Other Genetics Pattern Phenotype Population Process Property Proteins Public Health RNA RNA Interference Receptor Gene Regulation Research Research Proposals Selection Bias Sensory Sequence Analysis Sequence Homology Specific qualifier value Staging Stem Cell Research System Testing Thalassemia Transcriptional Regulation Transfection Undifferentiated base comparative epigenome frontier genome-wide histone methyltransferase imprint in vivo insight interest nerve stem cell neuron development novel olfactory receptor precursor cell progenitor programs public health relevance receptor receptor expression research study therapeutic gene trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): The genome is the cardinal instrument of development that encodes the genetic parts and programs of an organism. With the sequencing of many genomes now complete, a next great frontier in the quest to understand the relationships between genotype and phenotype is to decipher how genome information is regulated. This frontier encompasses two essential attributes: regulatory code "hardwired" in genomes that specify spatial and temporal patterns of gene expression, and epigenetic influences that specify biological context to which a genome responds. This proposal investigates a complex odorant receptor (OR) gene regulatory system that is likely to reveal both novel genetic and epigenetic properties of the genome, and thus provide additional insights into how transcriptional regulation is coordinated genome-wide. Using cell lines derived from pre-neuronal progenitors, our experiments will provide insights into the deterministic and stochastic properties underlying mutually exclusive OR expression during the development of olfactory sensory neurons (OSNs). Specifically, we will characterize restricted OR expression potential in OSN progenitors, determine whether singular OR selection utilizes iterative regulatory mechanisms, elucidate epigenetic contributions to OR co-regulation, and investigate the biological significance of OR RNA nuclear localization. Broadly, these studies will contribute to our knowledge about the structural organization of genomes and the "histone code" as it pertains to gene co- regulation and cell differentiation. The development and characterization of an OSN cell culture system should have far-reaching utility to the neuroscience community, especially considering that olfactory neurons are one of the only known central neuron types in mammals that are capable of regeneration throughout the life of an organism. Research on epigenetic regulation also has far-reaching implications to the medical community, since imprinting-related diseases (e.g., Beckwith-Wiedemann syndrome), oncogenic transformation, and other genetic disorders (e.g., Thalassemia) are associated with perturbation of normal chromatin states. In total, this project will utilize and further develop a promising in vitro system for studying OR expression and OSN development, provide some of the first data on the OR epigenome, and contribute to our understanding of gene co-regulatory programs inherent in our genome.

描述（由申请人提供）：基因组是编码生物体遗传部分和程序的主要发育工具。随着许多基因组的测序现已完成，了解基因型和表型之间关系的下一个重要前沿是破译基因组信息的调节方式。这一前沿包含两个基本属性：基因组中“硬连线”的调控代码，指定基因表达的空间和时间模式，以及表观遗传影响，指定基因组响应的生物背景。该提案研究了复杂的气味受体（OR）基因调控系统，该系统可能揭示基因组新的遗传和表观遗传特性，从而为转录调控如何在全基因组范围内协调提供更多见解。使用源自前神经元祖细胞的细胞系，我们的实验将深入了解嗅觉感觉神经元 (OSN) 发育过程中互斥 OR 表达背后的确定性和随机特性。具体来说，我们将表征 OSN 祖细胞中限制性 OR 表达潜力，确定单一 OR 选择是否利用迭代调节机制，阐明对 OR 共调节的表观遗传贡献，并研究 OR RNA 核定位的生物学意义。从广义上讲，这些研究将有助于我们了解基因组的结构组织和“组蛋白密码”，因为它涉及基因共调节和细胞分化。 OSN细胞培养系统的开发和表征应该对神经科学界具有深远的实用性，特别是考虑到嗅觉神经元是哺乳动物中唯一已知的能够在生物体整个生命周期再生的中枢神经元类型之一。表观遗传调控的研究对医学界也具有深远的影响，因为印记相关疾病（例如贝克威斯-维德曼综合征）、致癌转化和其他遗传性疾病（例如地中海贫血）与正常染色质状态的扰动有关。总的来说，该项目将利用并进一步开发一个有前景的体外系统来研究 OR 表达和 OSN 发育，提供一些有关 OR 表观基因组的首批数据，并有助于我们了解基因组中固有的基因共调控程序。