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：
7048771
负责人：
MICHAEL D UHLER
金额：
$ 61.27万
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 2009-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 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 embryonic 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-genic 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.

描述（由申请人提供）：脊椎动物神经系统内神经元的精确分化是由复杂的转录因子相互作用的复杂遗传程序，以及对环境提示对这些相互作用的调节。尽管在神经元分化中已经表征了许多特定转录因子和信号通路的作用，但我们对所涉及的详细机制的理解远非完整。该建议采用了几种哺乳动物基因组的基因组序列信息，这是脊椎动物神经系统发育在整个进化过程中都高度保守的基本观察，功能基因组学的最新发展提出了对神经元差异的高通量功能基因组分析。在该提案中要检验的假设是，神经元分化过程中诱导基因的进化保守序列对于神经元诱导的编排很重要。在第一个特定目的中，P19胚胎癌细胞将被诱导进行神经元分化，并将进行微阵列杂交研究，以识别转录调节的基因。在第二个特定目的中，将分析使用高通量微阵列TORTOCTION在P19中的高通量微阵列转染法，分析了最近提出的小鼠基因组的进化保守的非基因序列（CNG），以代表顺式调节序列的簇进行转录调控。细胞。在第三个特定目的中，将表征蛋白激酶和转录因子在这些顺式作用序列调节中的作用。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，以及特定信号转导途径在调节其转录激活中的作用。这些研究的结果对于未来治疗神经退行性疾病的治疗方法将很重要，包括阿尔茨海默氏症和帕金森氏病。