Functional Genomic Studies of Neuronal Differentiation

神经元分化的功能基因组研究

基本信息

批准号：
7560357
负责人：
MICHAEL D UHLER
金额：
$ 56.66万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-15 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7560357
关键词：
ASCL1 gene Alzheimer&apos s Disease Binding Sites Bioinformatics Biological Models Biological Process Cell Differentiation process Cells Cis-Acting Sequence Collection Complex Conserved Sequence Cues Development Down-Regulation Elements Embryo Event Evolution Foundations Future Gene Expression Genes Genetic Programming Genie Genomics In Situ Hybridization Laboratories Ligands Malignant Epithelial Cell Mediating Methodology Methods Nervous system structure Neurodegenerative Disorders Neuronal Differentiation Neurons Parkinson Disease Plasmids Process Protein Kinase Proteins RNA Interference Reagent Regulation Regulatory Pathway Reporter Research Personnel Role Signal Pathway Signal Transduction Pathway Small Interfering RNA Specific qualifier value Stem cells Testing Therapeutic Transcriptional Activation Transcriptional Regulation Transfection Tretinoin base biological systems extracellular functional genomics in vivo mammalian genome mouse genome nerve stem cell nervous system development neuron development progenitor programs research study response transcription factor vector

项目摘要

The precise differentiation of neurons within the vertebrate nervous system is specified by a complex genetic program of transcription factor interactions, as well as modulation of these interactions by environmental cues. Although the roles of many specific transcription factors and signaling pathways have been characterized in neuronal differentiation, our understanding of the detailed mechanisms involved is still far from complete. This proposal employs genomic sequence information of several mammalian genomes, the fundamental observation that vertebrate nervous system development is highly conserved throughout evolution, and recent developments in functional genomics to propose a high-throughput functional genomic analysis of neuronal differentiation. The hypothesis to be tested in this proposal is that evolutionary conserved sequences surrounding genes induced during neuronal differentiation are important to the orchestration of neuronal induction. In the first specific aim,P19 embyronic carcinoma cells will be induced to undergo neuronal differentiation and microarray hybridization studies will be carried out to identify genes that are transcriptionally regulated. In the second specific aim, evolutionarily conserved non-genie sequences (CNGs) of the mouse genome, that have recently been proposed to represent clusters of cis- regulatory sequences, will be analyzed for transcriptional regulation using a high-throughput microarray transfection method in P19 cells. In the third specific aim, the role of protein kinases and transcription factors in the regulation of these cis- acting sequences will be characterized. The end result of these studies will be a detailed understanding of important cis-regulatory sequences of neuronally induced genes and the role of specific signal transduction pathways in the modulation of their transcriptional activation. The results of these studies will be important for future therapeutic approaches to treatment of neurodegenerative diseases including Alzheimer's and Parkinson's diseases.

脊椎动物神经系统内神经元的精确分化是由复合物指定的转录因子相互作用的遗传程序，以及对这些相互作用的调节环境提示。尽管许多特定转录因子和信号通路的作用具有在神经元分化中的表征，我们对所涉及的详细机制的理解仍然是远离完成。该建议采用了几种哺乳动物基因组的基因组序列信息，脊椎动物神经系统发育的基本观察是高度保守的进化以及功能基因组学的最新发展提出了高通量功能基因组神经元分化的分析。在此提议中要检验的假设是进化神经元分化过程中诱导基因的保守序列对神经元诱导的管弦乐。在第一个特定目的中，将诱导p19 embyronic癌细胞将进行神经元分化和微阵列杂交研究以识别基因受转录调节。在第二个特定目标中，进化保守的非基因小鼠基因组的序列（CNG），最近被提出代表顺式的簇调节序列将使用高通量微阵列分析转录调节 p19细胞中的转染方法。在第三个特定目的中，蛋白激酶和转录的作用这些序列序列的调节中的因素将被表征。这些研究的最终结果将是对神经诱导基因的重要顺式调节序列的详细理解和特定信号转导途径在其转录激活调制中的作用。结果这些研究对于未来的治疗方法对神经退行性的治疗非常重要包括阿尔茨海默氏症和帕金森氏病在内的疾病。