Neuron - glial communication and brain aging

神经元-胶质细胞通讯和大脑衰老

• 批准号: 8721315
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721315
• 关键词: Address; Adhesions; Age; Age-Months; Aging; Astrocytes; Binding; Brain; C57BL/6 Mouse; CX3CL1 gene; Cell Culture Techniques; Cell Death; Cells; Chemotaxis; Chronic; Cleaved cell; Cognitive; Cognitive deficits; Collaborations; Communication; Dependovirus; Disease; Down-Regulation; Early Intervention; Endothelial Cells; Environment; Event; Forms Controls; Fractalkine; Functional disorder; Future; Hippocampus (Brain); IL4 gene; Immune; Impaired cognition; Incidence; Inflammatory; Integral Membrane Protein; Interleukin-1; Interleukin-10; Interleukin-13; Intervention; Knockout Mice; Lead; Ligands; Ligation; Literature; Long-Term Potentiation; Measures; Membrane; Microglia; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Phenotype; Play; Process; Production; Property; Publishing; Rain; Rattus; Regulation; Rest; Risk Factors; Role; Serotyping; Severities; Signal Transduction; Signaling Molecule; Stimulus; Surveys; Synaptic plasticity; Testing; Therapeutic; Time; Tumor Necrosis Factor-alpha; Variant; Work; age related; aged; aging brain; chemokine; cognitive function; cytokine; dentate gyrus; expression vector; innate immune function; monocyte; mutant; neurogenesis; normal aging; novel; novel strategies; prevent; receptor; relating to nervous system; research study; response; tool; vector

A major theme of this project is understanding the causes and conditions that lead to a state of chronic up- regualtion of pro-inflammatory process in aging that are the backround within which 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 results in down regulation of 11-1 ß, TNFα and other pro-inflammatory cytokines. We will examine regulation of CX3CL1 as it is present as both a cleaved soluble form and a membrane bound form. There is evidence that the membrane bound form and the soluble form control different aspects of immune regulation, however this is poorly understood. To address this question we have generated rAAV9 vectors that express 1 )soluble, 2) native and 3) a mutant uncleaved CX3CL1. We will 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 cognitive function in aged mice and CX3CL1 deficient mice to determine 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 neural specific versus astrocyte specific expression of CX3CL1 alters the functional properties. CX3CL1 is normally epxressed in nuerons, hoever under certain conditions it has been 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 observed blunted responses to iL4/IL13 in the aged brain. We will examine this in the CX3CR1 null and CX3CL1 null mice as well as normal aged C57BL/6 mice. We will isolate primary microglia for ex vivo cell culture experiments to determine if any changes in regulation of M1 and M2 responses are cell autonomous or non cell autonomous.

该项目的一个主题是了解导致慢性上升状态的原因和条件 衰老过程中促炎症过程的调节，这是神经退行性疾病的背景 疾病发生。我们已经证明，趋化因子 fractalkine (FKN) 的丢失是细胞中的一个早期事件。 大脑老化，这会导致对 ILI3 和 TNFa 等促炎症信号的偏向。 Fractalkine (CX3CL1) 在神经元中表达，受体 (CX3CR1) 在小胶质细胞上表达。连接 CX3CR1 导致 11-1β、TNFα 和其他促炎细胞因子的下调。我们将检查 CX3CL1 的调节，因为它以裂解的可溶形式和膜结合形式存在。有 有证据表明膜结合形式和可溶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，我们生成了表达的 rAAV9 载体 1)可溶的，2)天然的和3)突变的未切割的CX3CL1。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调节神经的作用 可塑性通过老年小鼠的神经发生和长时程增强（LTP）以及认知功能来衡量 CX3CL1 缺陷小鼠以确定在早期（12 个月）替换 FKN 是否会导致国王 持久调节小胶质细胞功能，防止先天免疫功能随着年龄的增长而增加，并预防 神经可塑性和认知功能丧失。在目标 2 中，我们将检查神经特异性与星形胶质细胞是否 CX3CL1 的特异性表达会改变功能特性。 CX3CL1 通常在核子中表达， 然而，在某些条件下，它已在星形胶质细胞中观察到。在目标 3 中，我们将进一步探讨 CX3CL1 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，正如我们所知道的 观察到老年人大脑对 iL4/IL13 的反应减弱。我们将在 CX3CR1 null 和 CX3CL1 缺失小鼠以及正常年龄的 C57BL/6 小鼠。我们将分离原代小胶质细胞作为离体细胞 培养实验以确定 M1 和 M2 反应调节的任何变化是否是细胞自主的 或非细胞自主。