Mechanisms and Function of NF-kappaB Activation at Dendritic Spines

树突棘 NF-kappaB 激活的机制和功能

• 批准号: 8220924
• 负责人: MOLLIE Katherine MEFFERT
• 金额: $ 32.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-06 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220924
• 关键词: Adult; Alzheimer' s Disease; Apoptotic; Area; Binding; Biochemical; Biological Models; Brain; Brain Diseases; Cell Nucleus; Dendritic Spines; Diagnosis; Dominant-Negative Mutation; Environment; Excitatory Synapse; Gene Expression; Genetic Transcription; Health; Hippocampus (Brain); Image; Investigation; Knock-out; Knowledge; Learning; Life; Light; Memory; Morphology; Mus; NF-kappa B; Neurodegenerative Disorders; Neurologic; Neurons; Pathway interactions; Physiological; Physiology; Process; RNA Interference; Recruitment Activity; Regulation; Research; Research Proposals; Role; Shapes; Signal Transduction; Stroke; Synapses; Testing; Tissues; Transgenic Mice; Vertebral column; base; density; dimer; neonate; nervous system disorder; neurodevelopment; overexpression; postsynaptic; programs; protein protein interaction; repaired; research study; response; response to injury; synaptic function; synaptogenesis; transcription factor

DESCRIPTION (provided by applicant): Plasticity at synapses is a fundamental process believed to underlie the remarkable ability of our brains to adapt to changing environments and new challenges. It is involved in neural development, learning and memory, and response to injury, as well as accompanying the apoptotic process common to many neurodegenerative diseases. Synaptic remodeling, the process of changing the size, shape, number or connectivity of synapses, occurs during plasticity and is thought to be a critical mechanism regulating synaptic function. In the mammalian brain, the majority of excitatory synapses occur on dendritic protrusions termed spines. This research proposal will investigate how the nuclear factor kappa B (NF-:B) transcription factor may function to regulate synaptic contacts received by hippocampal neurons. Interestingly, NF-:B is itself located at synapses and can be activated by excitatory activity. These investigations will explore the relationship between pathways of synaptic remodeling and NF-:B activation, and the resulting changes in gene expression which may augment dendritic spines and postsynaptic responses. The hippocampus has been selected as a model system for studying the effects of neuronal NF-:B on dendritic spine and synapse number because it is a well-defined area of both physiological (learning and memory) as well as pathological (stroke, Alzheimer's disease) neuronal function. The studies will use hippocampal tissue from both adult mice and neonates, including transgenic mice. Specifically, experiments will focus on how the NF-:B transcription factor may be recruited to or tethered in dendritic spines, the pathway of NF-:B activation at synapses, and the regulation of dendritic spine density and morphology by NF-:B with potential functional effects on synaptic physiology. PUBLIC HEALTH RELEVANCE: The knowledge gained from this research will create a better understanding of the endogenous signaling cascades responsible for transcription factor modulation of synapse formation and synaptic remodeling. These processes are of fundamental neurological consequence for brain plasticity and repair and are hypothesized to be a structural basis underlying learning and memory. In addition, it is the aim of these investigations to shed light on how pathways of synaptic remodeling, like the NF-?B transcription factor itself, could operate in both normal brain function as well as in neurological disorders and to provide potential targets for diagnosing and treating brain disease.

描述（由申请人提供）：突触的可塑性是一个基本过程，据信是我们大脑适应不断变化的环境和新挑战的卓越能力的基础。它参与神经发育、学习和记忆、对损伤的反应，以及伴随许多神经退行性疾病常见的细胞凋亡过程。突触重塑是改变突触大小、形状、数量或连接性的过程，发生在可塑性过程中，被认为是调节突触功能的关键机制。在哺乳动物大脑中，大多数兴奋性突触发生在称为棘的树突状突起上。该研究计划将研究核因子 kappa B (NF-:B) 转录因子如何发挥作用来调节海马神经元接收的突触接触。有趣的是，NF-:B 本身位于突触处，可以被兴奋性活动激活。这些研究将探讨突触重塑途径和 NF-:B 激活之间的关系，以及由此产生的基因表达变化，这可能会增强树突棘和突触后反应。海马体已被选为研究神经元 NF-:B 对树突棘和突触数量影响的模型系统，因为它是生理（学习和记忆）以及病理（中风、阿尔茨海默病）神经元功能的明确区域。这些研究将使用成年小鼠和新生儿（包括转基因小鼠）的海马组织。具体来说，实验将重点关注 NF-:B 转录因子如何被招募或束缚在树突棘中、突触处 NF-:B 激活的途径，以及 NF-:B 对树突棘密度和形态的调节以及对突触生理学的潜在功能影响。公共健康相关性：从这项研究中获得的知识将有助于更好地理解负责突触形成和突触重塑的转录因子调节的内源信号级联。这些过程对大脑可塑性和修复具有基本的神经学影响，并且被假设为学习和记忆的结构基础。此外，这些研究的目的是阐明突触重塑途径（如 NF-κB 转录因子本身）如何在正常脑功能和神经系统疾病中发挥作用，并为诊断和治疗脑疾病提供潜在靶点。