Neuron - glial communication and brain aging

神经元-胶质细胞通讯和大脑衰老

• 批准号: 9084462
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9084462
• 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; TNF gene; Testing; Therapeutic; Time; Variant; Work; age related; aged; aging brain; chemokine; cognitive function; cytokine; dentate gyrus; expression vector; innate immune function; monocyte; mutant; neurogenesis; neurotransmission; 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.

该项目的一个主要主题是了解导致长期上升状态的原因和条件 衰老中的促炎过程的调节是神经变性的背景 疾病发生。我们已经证明了趋化因子分裂（FKN）的损失是早期事件 脑老化，这会引起对促炎性信号（例如ILI3和TNFA）的偏见。 分裂（CX3CL1）在神经元中表达，受体（CX3CR1）在小胶质细胞上。连接 CX3CR1导致减少11-1β，TNFα和其他促炎细胞因子的调节。我们将检查 CX3CL1的调节既是裂解的固体形式和膜结合形式。有 膜结合形式和固体形式控制免疫调节的不同方面的证据， 但是，这是很众所周知的。为了解决这个问题，我们生成了表达的raav9载体 1）可溶，2）天然和3）突变体未溶解的CX3CL1。我们将使用这些独特而新颖的工具来 了解这些形式的FKN在控制小胶质功能及其调节神经元的作用中的作用 在老年小鼠和 CX3CL1缺乏小鼠以确定FKN在早期（12个月）是否会导致国王 小胶质功能的持久调节，并防止随着年龄的年龄和预遵循A的先天免疫功能的提高 神经可塑性和认知功能的丧失。在AIM 2中，我们将检查神经特异性与星形胶质细胞是否 CX3CL1的特定表达改变了功能特性。 CX3CL1通常在nuerons中粘着 在某些条件下，已经在星形胶质细胞中观察到。在AIM 3中，我们将进一步研究 CX3CL1及其接收器的作用可能随着年龄的增长与ML和M2对刺激的响应相互作用，因为我们 观察到对老年大脑中IL4/IL13的钝化反应。我们将在CX3CR1 null和 CX3CL1 NULL小鼠以及正常老化的C57BL/6小鼠。我们将分离出离体细胞的主要小胶质细胞 培养实验以确定M1和M2响应调节的任何变化是否是细胞自主 或非细胞自主。

项目成果

Proteomic anaysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response.

• DOI: 10.1186/s12974-017-0840-7
• 发表时间: 2017-05-03
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Flowers A;Bell-Temin H;Jalloh A;Stevens SM Jr;Bickford PC
• 通讯作者: Bickford PC

Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.

• DOI: 10.1186/s12974-015-0386-5
• 发表时间: 2015-09-02
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Febinger HY;Thomasy HE;Pavlova MN;Ringgold KM;Barf PR;George AM;Grillo JN;Bachstetter AD;Garcia JA;Cardona AE;Opp MR;Gemma C
• 通讯作者: Gemma C