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.

这个项目的一个主要主题是了解导致慢性上升状态的原因和条件

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