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（逐字研究申请人的摘要）：此K02申请是 为支持我的薪水和职业发展而写。我一直是会员 约翰·霍普金斯大学神经科学系的学院 过去四年半的医学院。长期 我的研究的目的是阐明神经元的作用机理 控制神经系统发展和生存的生长因子 成人神经元。神经生长因子（NGF）是原型目标衍生的 神经营养生长因子。除了它在 神经发育，NGF可以促进成人神经元种群的生存， 包括通常在患有 阿尔茨海默氏病。因此，我们的工作应该提供有关 神经发育以及对心理至关重要的神经元的维护 健康。 神经营养蛋白激活转录因子CREB（CAMP响应元件 结合蛋白）通过在转录上诱导CREB的磷酸化 监管地点，Ser-133。此外，Creb Ser-133的磷酸化为 由新生儿中的逆行传播神经营养信号调节 交感神经元。最后，初步结果表明Creb或 密切相关的Creb家族成员，对于NGF诱导至关重要 C-Fos的转录。由于许多（如果不是大多数），NGF敏感的基因包含 CREB绑定位点在其上游监管区域内，很可能 Creb和Creb家族成员是一般核的关键调解人 对目标衍生的NGF的响应。作为了解NGF的总体目标的一部分 调节有助于神经元分化的基因表达的调节， 可塑性和生存，拟议研究的具体目的是：1） 表征逆行NGF信号传导到转录因子的机制 CREB和其他核靶标在发展交感神经元中； 2）到 确定逆行NGF信号向CREB和CREB和 其他核目标，3）确定CREB和CREB的要求 NGF信号转导的家庭成员。拟议的研究将在一起 提供有关NGF信号转导机理的洞察力，分子 神经发育的基础，以及对成年神经元存活的控制， 容易在具有衰弱的神经退行性疾病中死亡 对心理健康的深远影响。