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这个项目的一个主要主题是了解导致慢性UP状态的原因和条件。 在WHK:H神经退行性变的背景下,衰老中促炎过程的调节 疾病就会发生。我们已经证明趋化因子Fractalkine(FKN)的丢失是一种早期事件 大脑老化,这加速了对促炎信号的偏爱,如ILI3和TNFa。 Fractalkine(CX3CL1)表达于神经元,其受体(CX3CR1)位于小胶质细胞上。结扎术 CX3CR1下调11-1p、TNFa等促炎细胞因子的表达。我们将研究 对CX3CL1的调控,因为它同时以裂解的可溶性Fonn和膜结合的Fomi的形式存在。的确有 有证据表明,膜结合形式和可溶性孔洞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rAAVQ向量,以表达 1)可溶的,2)天然的和3)未裂解的突变体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在控制小胶质细胞功能中的作用及其对神经调节的作用 以神经发生、长时程增强(LTP)和cf功能为指标测量衰老小鼠的可塑性 CX3CL1缺陷小鼠在早期(12个月)更换FKN是否会导致国王 持续调节小胶质细胞功能,防止天然免疫功能随年龄和年龄的增加而增加 神经可塑性和认知功能丧失。在目标2中,我们将检查神经细胞和星形胶质细胞是否具有L的特异性 CX3CL1的特异性表达改变了其功能特性。CX3CL1通常用神经符号表示, 但在某些条件下,星形胶质细胞中还没有观察到这种现象。在目标3中,我们将进一步了解 CX3CL1及其受体可能与M1和M2对刺激的反应随着年龄的增长而相互作用,就像我们所做的那样 观察老年人大脑对IL4/IL13的迟钝反应。我们将在TFIE CX3CR1 NULL和 CX3CL1基因缺失小鼠以及未老化的C57BL/6小鼠。我们将为体外细胞分离原代小胶质细胞 培养实验确定L 1和M2反应的调节是否有任何变化是细胞自主的 或非细胞的自体血细胞。 相关性(请参阅实例): 衰老是许多神经退行性疾病的主要危险因素,也可能与 认知减慢^。了解大脑中的关键分子,这些分子在大脑老化过程中潜藏着变化,使 大脑对疾病的易感性是至关重要的,并可能导致新的方法来减少发病率或 神经退行性疾病的严重程度和认知功能随年龄的下降
英文摘要
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
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会议论文
Aging and Innate immune system resilience in TBI
  • 批准号:
    10616497
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2022
  • 负责人:
    PAULA C BICKFORD
  • 依托单位:
Aging and Innate immune system resilience in TBI
  • 批准号:
    10369760
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2022
  • 负责人:
    PAULA C BICKFORD
  • 依托单位:
ShEEP Request for QuantStudio 12K Flex Real-Time PCR system
  • 批准号:
    9796289
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2019
  • 负责人:
    PAULA C BICKFORD
  • 依托单位:
BLRD Research Career Scientist Award Application
  • 批准号:
    10618267
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2018
  • 负责人:
    PAULA C BICKFORD
  • 依托单位:
国内基金
海外基金
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
  • 依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
    雷芬芳
  • 依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    万荣
  • 依托单位: