NEUROTROPHIN REGULATION OF CRE-BINDING PROTEIN

神经营养因子对 Cre 结合蛋白的调节

• 批准号: 6090007
• 负责人: David D GINTY
• 金额: $ 2.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-10 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6090007
• 关键词: PC12 cells; binding sites; biological signal transduction; cAMP response element binding protein; developmental neurobiology; gene expression; genetic regulation; genetic transcription; microarray technology; mutant; nerve growth factors; neurons; neurotrophic factors; northern blottings; phosphorylation; polymerase chain reaction; protein structure function; reporter genes; transcription factor; transfection

DESCRIPTION (Verbatim from the Applicant's Abstract): This K02 application is written for support of my salary and career development. I have been a member of the faculty of the Department of Neuroscience, John Hopkins University School of Medicine for the past four and one-half years. The long-term objective of my research is to elucidate the mechanism of action of neuronal growth factors that control development of the nervous system and survival of adult neurons. Nerve growth factor (NGF) is the prototypical target-derived neurotrophic growth factor. In addition to its prominent role during neurodevelopment, NGF can promote survival of populations of adult neurons, including septal cholinergic neurons that normally die in patients with Alzheimer's disease. Thus, our work should provide insight into neurodevelopment as well as maintenance of neurons that are critical for mental health. Neurotrophins activate the transcription factor CREB (cAMP-response element binding protein) by inducing phosphorylation of CREB on a transcriptional regulatory site, Ser-133. In addition, phosphorylation of CREB Ser-133 is regulated by a retrogradely propagated neurotrophin signal in neonatal sympathetic neurons. Lastly, preliminary results indicate that CREB, or a closely related CREB family member, is critical for NGF induction of transcription of c-fos. Since many, if not most, NGF-sensitive genes contain CREB binding sites within their upstream regulatory regions, it is likely that CREB and CREB family members are critical mediators of the general nuclear response to target-derived NGF. As part of our overall goal to understand NGF regulation of expression of genes that contribute to neuronal differentiation, plasticity and survival, the specific aims of the proposed research are: 1) To characterize the mechanisms of retrograde NGF signaling to transcription factor CREB and other nuclear targets in developing sympathetic neurons; 2) To determine the functional consequences of retrograde NGF signaling to CREB and other nuclear targets, and 3) To establish the requirement of CREB and CREB family members in NGF signal transduction. Together, the proposed research will provide insight into the mechanism of NGF signal transduction, the molecular basis of neurodevelopment, and the control of survival of adult neurons, which are susceptible to death in debilitating neurodegenerative diseases that have profound influence on mental health.

描述（来自申请人摘要的逐字）：本K 02申请是 这是为了支持我的薪水和职业发展。我是一名 约翰霍普金斯大学神经科学系教授 医学院在过去的四年半。长期 我的研究目的是阐明神经元的作用机制， 控制神经系统发育和存活的生长因子 成年神经元神经生长因子（NGF）是典型的靶向衍生的 神经营养生长因子除了在期间发挥的突出作用外， 神经发育，NGF可以促进成年神经元群体的存活， 包括正常情况下死于 老年痴呆症因此，我们的工作应该提供洞察力， 神经发育以及神经元的维持，这些神经元对精神发育至关重要。 健康 神经营养因子激活转录因子CREB（cAMP反应元件 结合蛋白）通过诱导CREB在转录水平上的磷酸化， 调节位点，Ser-133。此外，CREB Ser-133的磷酸化是一个重要的信号通路。 在新生儿中由逆行传播的神经营养因子信号调节 交感神经元最后，初步结果表明，CREB，或 与CREB家族成员密切相关，对于NGF诱导 转录c-fos。由于许多（如果不是大多数）神经生长因子敏感基因含有 CREB结合位点的上游调控区，很可能， CREB和CREB家族成员是一般核转录的关键介质。 对目标衍生的NGF的反应。作为我们了解NGF的总体目标的一部分， 调节有助于神经元分化的基因的表达， 可塑性和生存，建议研究的具体目标是：1） 探讨NGF信号传导至转录因子的机制 CREB和其他核靶点在发育中的交感神经元中; 2） 确定逆行NGF信号传导至CREB的功能后果， 其他核目标，以及3）建立CREB和CREB的要求 家族成员参与NGF信号转导。总之，拟议的研究将 提供深入了解神经生长因子信号转导的机制， 神经发育的基础，以及成年神经元存活的控制， 容易死于神经退行性疾病， 对心理健康有深远影响。