Sp1, kappa-B enhancers and transcriptions in neurons

描述（由申请人提供）：全基因组基因测序的生物科学注入加速了发现，但完全利用这些信息需要基因调控的详细信息。这一点在神经系统中表现得最为明显，在神经系统中，环境与遗传信息的相互作用以学习和记忆的形式出现。谷氨酸在这些过程中是一种重要的神经递质，但在一些神经退行性疾病中也成为一种神经毒素。已发表的文献表明，谷氨酸受体的激活可诱导中枢神经系统神经元的转录因子NF-kappa-B；谷氨酸输入也与这些细胞中NF-kappa-B的明显构成性基础活性有关。然而，为支持这一建议而进行的更严格的测试表明，谷氨酸不会激活从大脑皮层培养的神经元中NF-kappa-B dna结合。此外，唯一构成NF-kappa-B靶点结合的因子是Sp1和相关蛋白，谷氨酸降低了这种活性。总之，这些结果表明NF-kappa-B不是先前认为的谷氨酸应答转录因子。但相当多的证据仍然表明，kappa-B元素控制着对神经元生存能力重要的基因。以下假设将被验证：Sp1相关蛋白通过与kappa-B元素结合影响促生存基因，而谷氨酸毒性涉及Sp1和NF-kappa-B对kappa-B元素结合的减少。首先，谷氨酸诱发的抑制皮层神经元NF-kappa-B活性的事件将通过翻译后修饰和与其他蛋白质相互作用的测试来阐明。其次，研究NF-kappa-B在保护神经元抗谷氨酸毒性中的作用。第三，探索谷氨酸抑制sp1相关因子活性的机制。最后，sp1相关蛋白通过kappa-B顺式元件控制神经元转录的能力，特别是关于促进生存的基因，将被探索。这些研究应该阐明一个有争议的问题，即NF-kappa-B及其DNA靶点在大脑神经元中的作用。因此，这项工作可能对主要神经递质影响记忆、学习和兴奋毒性细胞死亡的遗传相关的机制产生直接影响，这些范式对人类心理健康具有相当重要的意义。

DESCRIPTION (provided by applicant): Infusion of the biological sciences with genetic sequencing of entire genomes has sped discovery, but complete utilization of this information awaits detailed information about gene regulation. Nowhere is this more apparent than in the nervous system, where environmental interactions with genetic information take the form of learning and memory. Glutamate is a paramount neurotransmitter in these processes, but also becomes a neurotoxin in several neurodegenerative conditions. Published literature suggests that activation of glutamate receptors can induce the transcription factor NF-kappa-B in CNS neurons; glutamatergic input has also been implicated in an apparent constitutive basal activity of NF-kappa-B in these cells. However, more stringent tests performed in support of this proposal indicate that glutamate does not activate NF-kappa-B DNA-binding in neurons cultured from the cerebral cortex. Furthermore, the only factors constitutively binding NF-kappa-B target sites are Sp1 and related proteins, and glutamate decreases this activity. Together, these results indicate that NF-kappa-B is not a glutamate-responsive transcription factor as previously thought. But considerable evidence still suggests that kappa-B elements control genes important for neuronal viability. The following hypothesis will be tested: Sp1-related proteins influence survival-promoting genes through binding to kappa-B elements, and glutamate toxicity involves a reduced binding of kappa-B elements by both Sp1 and NF-kappa-B. First, glutamate-evoked events that squelch NF-kappa-B activity in cortical neurons will be elucidated through tests of post-translational modifications and interactions with other proteins. Second, the role of NF-kappa-B in protection of neurons against glutamate toxicity will be examined. Third, mechanisms by which glutamate suppresses the activity of Sp1-related factors will be explored. Finally, the ability of Sp1-related proteins to control neuronal transcription through kappa-B cis elements, with particular regard to survival-promoting genes, will be explored. These studies should shed light on a contentious issue, namely, the role of NF-kappa-B and its DNA target sites in cerebral neurons. As such, this body of work could have direct impact on the mechanisms by which a major neurotransmitter impacts on the genetic correlates of memory, learning, and excitotoxic cell death, paradigms of considerable significance to human mental health.