Neuron - glial communication and brain aging

神经元-胶质细胞通讯和大脑衰老

• 批准号: 8531398
• 负责人: PAULA C BICKFORD
• 金额: $ 34.55万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531398
• 关键词: Address; Age; Age-Months; Aging; Astrocytes; Binding; Brain; C57BL/6 Mouse; CX3CL1 gene; Cell Culture Techniques; Cell Death; Cells; Chronic; Cleaved cell; Cognitive; Cognitive deficits; Communication; Disease; Down-Regulation; Event; Fractalkine; Functional disorder; Future; Hippocampus (Brain); IL4 gene; Immune; Impaired cognition; Incidence; Inflammatory; Integral Membrane Protein; Interleukin-13; Intervention; Knockout Mice; Lead; Ligands; Ligation; Literature; Long-Term Potentiation; Measures; Membrane; Microglia; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Phenotype; Play; Process; Property; Rattus; Regulation; Risk Factors; Role; Serotyping; Severities; Signal Transduction; Specific qualifier value; Stimulus; Synaptic plasticity; Testing; Time; Variant; Virus; aged; aging brain; chemokine; cognitive function; cytokine; dentate gyrus; expression vector; innate immune function; monocyte; mutant; neurogenesis; novel; prevent; receptor; research study; response; tool; vector

A major theme of this project is understandli>g the causes and condittons that lead to a state of chronic up- regualtion of pro-inflammatory process in aging that are the backround within whk:h neurodegeneartive disease occurs. We have demonstrated that loss of the chemokine fractalkine (FKN) is an early event in brain aging and that this precipitates a bias towards pro-inflammatory signals such as ILI3 and TNFa. Fractalkine (CX3CL1) is expressed in neurons and the receptor (CX3CR1) is on microglia. Ligation of CX3CR1 resullts in down regulation of 11-1 p, TNFa and other pro-inflammatory cytokines. We will examine regulation of CX3CL1 as it is present as both a cleaved soluble fonn and a membrane bound fomi. There is evidence that the membrane bound form and the soluble forni control different aspects of immune regulation, however this is poorly understood. To address this questton we have generated rAAVQ vectors that express 1 )soluble, 2) native and 3) a mutant uncleaved CX3CL1. We wUI use these unique and novel tools to understand the role these forms of FKN in control of microglial function and its role to regulate neural plasticity measured as neurogensis and long term potentiaion (LTP) and cf^ntiive function in aged mice and CX3CL1 deficient mice to dtermine if replacement of FKN at an early age (12 months) will lead to king lasting regulation of microglial function and prevent increased innate immune function with age and preverit a loss in neural plasticity and cognitive function. In aim 2 we will examine if neurr^l specify versus astrocyte specific expression of CX3CL1 alters the functional properties. CX3CL1 is normally epxressed in nuerons, hoever under certain condittons it has t)een observed in astrocytes. In aim 3 we will then look further at the role of CX3CL1 and its receptor as it may interact with Ml and M2 responses to stimuli with age, as we have obsen^ed blunted responses to iL4/IL13 in the aged brain. We will examine this in tfie CX3CR1 null and CX3CL1 null mice as well as nonnai aged C57BL/6 mice. We will isolate primary microglia for ex vivo cell culture experiments to detemnine if any changes in regulation of l\^1 and M2 responses are cell autonomous or non cell autononwus. RELEVANCE (See instnjctions): Aging is a primary risk factor for many neurodegenerative diseases and also can be associated with cognitive slowir^. Understanding key molecules in the brain that underly changes in brain aging that make the brain more suceptible to disease is critical and can lead to new approacfies to reduce the incidence or severity of neurodegenerative diseases and declines in cognitive function with age

这个项目的一个主要主题是了解导致慢性疾病状态的原因和条件， 衰老中促炎过程的调节是whk：h神经退行性变的背景 疾病发生。我们已经证明，趋化因子Fractalkine（FKN）的缺失是一个早期事件， 脑老化，并且这沉淀了对促炎信号如ILI 3和TNFa的偏好。 Fractalkine（CX 3CL 1）在神经元中表达，受体（CX 3CR 1）在小胶质细胞上。结扎 CX 3CR 1可下调IL-1 β、TNF α和其他促炎细胞因子的表达。我们将研究 调节CX 3CL 1，因为它以裂解的可溶性形式和膜结合形式存在。有 有证据表明膜结合形式和可溶性形式控制免疫调节的不同方面， 然而，人们对此知之甚少。为了解决这个问题，我们已经产生了表达 1）可溶的，2）天然的和3）突变的未切割的CX 3CL 1。我们将使用这些独特而新颖的工具， 了解这些形式的FKN在控制小胶质细胞功能中的作用及其在调节神经元功能中的作用。 在老年小鼠中，可塑性测量为神经发生和长时程增强（LTP）以及神经功能， CX 3CL 1缺陷小鼠，以确定是否在早期（12个月）更换FKN将导致国王 持久调节小胶质细胞功能，防止先天免疫功能随年龄增长而增加， 神经可塑性和认知功能丧失。在目标2中，我们将检查神经元和星形胶质细胞是否有特异性。 CX 3CL 1的特异性表达改变了功能特性。CX 3CL 1通常在神经元中表达， 但在某些条件下，在星形胶质细胞中尚未观察到。在目标3中，我们将进一步研究 CX 3CL 1及其受体的作用，因为它可能与M1和M2对年龄刺激的反应相互作用，正如我们所做的那样， 在老年人的大脑中观察到对IL 4/IL 13的反应迟钝。我们将在CX 3CR 1 null和 CX 3CL 1缺失小鼠以及非老龄C57 BL/6小鼠。我们将分离原代小胶质细胞用于体外细胞培养， 培养实验以确定在调节I1和M2反应中的任何变化是否是细胞自主的 或非细胞自动化。 相关性（参见说明）： 衰老是许多神经退行性疾病的主要风险因素，也可能与 认知迟钝了解大脑中的关键分子，这些分子是大脑衰老变化的基础， 大脑对疾病更敏感是至关重要的，可以导致新的方法来降低发病率， 神经退行性疾病的严重程度和认知功能随着年龄的增长而下降