Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
基本信息
- 批准号:10693590
- 负责人:
- 金额:$ 39.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-10 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAlteplaseAlternative SplicingAlzheimer&aposs DiseaseAnti-Inflammatory AgentsApolipoprotein EAstrocytesAttenuatedAutomobile DrivingBindingBrainBreedingCell surfaceCellsClinicalColitisDataDiseaseDisease ProgressionElementsFibrinolysisFunctional disorderFundingGene DeletionGene ExpressionGenesGenetic PolymorphismGoalsGrantHumanInflammationInflammation MediatorsInflammatoryInflammatory ResponseInterferon Type IIKnockout MiceLDL-Receptor Related Protein 1LigandsLipopolysaccharidesLipoprotein ReceptorLipoproteinsMAPT geneMacrophageMediatingMembraneMembrane MicrodomainsMetalloproteasesMicrogliaMusMutateN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNGFR ProteinNatural ImmunityNerve DegenerationNeurofibrillary TanglesNeuronsOligodendrogliaPathogenesisPathologicPathway interactionsPeptide HydrolasesPeripheralPhosphorylationPhysiologyPlasminogen ActivatorPlayPost-Translational Protein ProcessingPrPProbabilityProteinsReceptor SignalingRegulationRoleSignal PathwaySignal TransductionSodium Dextran SulfateSystemTLR2 geneTLR4 geneTLR7 geneTauopathiesTestingToll-like receptorsTransgenic MiceUnited States National Institutes of HealthWorkalpha 2-Glucoproteinscentral sensitizationexosomeextracellularextracellular vesiclesglial activationin vivoinhibitorinjuredknockout genemonocytemouse modelmutantneuroinflammationnovelpain processingparent grantpromoterreceptorresponsetau aggregationtau functiontau interaction
项目摘要
Project Summary/Abstract
Low Density Lipoprotein Receptor-related Protein-1 (LRP1) functions as an endocytic and cell-signaling receptor
for the fibrinolysis protease, tissue-type plasminogen activator (tPA). Binding of tPA to LRP1 in macrophages
generates an anti-inflammatory response in which the activity of multiple Toll-like Receptors is attenuated. This
response requires LRP1 co-receptors, including the NMDA Receptor, which is essential. Because LRP1 has
numerous structurally and functionally diverse ligands, it is extremely important to understand whether different
ligands generate distinct signaling responses. The microtubule-associated protein, TAU, is a recently identified
LRP1 ligand which accumulates in the CNS in various forms of neurodegeneration and is a major driver of the
pathophysiology observed in Alzheimer's Disease (AD). Using cultured macrophages, we have shown that TAU
elicits responses that are distinct from those elicited from tPA; in fact, TAU functions as an LRP1-dependent pro-
inflammatory factor. Neuro-inflammation is highly important in AD and we hypothesize that interaction of TAU
with microglial LRP1 in the brain is a major driver of microglial activation, neuro-inflammation, and AD pro-
gression. Mechanistically, we have evidence that TAU activates pathways that release LRP1 from the cell
surface, converting the anti-inflammatory membrane-anchored receptor into a highly pro-inflammatory soluble
derivative (shed LRP1). The major goal of this supplement to parent grant R01 HL136395 is to test our hypo-
thesis that the receptor system under study in the parent grant is subjugated by TAU in the CNS to drive neuro-
inflammation in AD. Two specific aims are proposed. In Specific Aim 1, we will characterize the interaction of
TAU with LRP1 in cultured microglia and test the hypothesis that this interaction stimulates LRP1 shedding,
which activates microglia and promotes inflammation. Although our previous work suggests that the activities of
LRP1 ligands are conserved in macrophages and microglia, it is imperative that we test this hypothesis directly
in microglia. The effects of TAU on LRP1 shedding, microglial physiology, cell-signaling, and inflammatory
mediator expression will be considered. Microglia will be isolated from adult conditional gene knock-out mice
to confirm the role of LRP1 and test whether co-receptors are involved. In Specific Aim 2, we will study the
effects of microglial LRP1 on neuro-inflammation and the pathophysiology that develops in transgenic mice that
express the P301S mutant of human TAU. These mice develop spontaneous TAU aggregates that are
eventually lethal and neuro-inflammation plays a central role in the pathogenesis of disease. Neutralization of
LRP1 expression in microglia in these mice will be accomplished by breeding with mice in which Lrp1 is deleted
conditionally under the control of promoter systems active in microglia. These studies represent an important
extension of R01 HL136395 with significant potential to generate an independent NIH-funded grant focusing on
a completely novel pathway for neuro-inflammation in AD.
项目总结/摘要
低密度脂蛋白受体相关蛋白-1(LRP 1)作为内吞和细胞信号受体发挥作用
纤溶蛋白酶,组织型纤溶酶原激活剂(tPA)。巨噬细胞中tPA与LRP 1的结合
产生抗炎反应,其中多种Toll样受体的活性减弱。这
反应需要LRP 1辅助受体,包括NMDA受体,这是必不可少的。因为LRP 1具有
许多结构和功能上不同的配体,理解是否不同是非常重要的。
配体产生不同的信号传导应答。微管相关蛋白TAU是最近发现的一种新的微管相关蛋白。
LRP 1配体以各种形式的神经变性在CNS中积累,并且是神经变性的主要驱动因素。
在阿尔茨海默病(AD)中观察到的病理生理学。使用培养的巨噬细胞,我们已经表明,TAU
与tPA引起的反应不同的诱发反应;事实上,TAU作为LRP 1依赖性前体发挥作用,
炎症因子神经炎症在AD中非常重要,我们假设TAU的相互作用
脑中的小胶质细胞LRP 1是小胶质细胞活化、神经炎症和AD前体的主要驱动因素。
格雷辛。从机制上讲,我们有证据表明TAU激活了从细胞中释放LRP 1的途径
表面,将抗炎膜锚定受体转化为高度促炎的可溶性
衍生物(脱落LRP 1)。本补充父母补助金R 01 HL 136395的主要目标是测试我们的低血糖,
论文认为,受体系统正在研究中的父母赠款是屈从于TAU在中枢神经系统,以驱动神经元,
AD炎症提出了两个具体目标。在具体目标1中,我们将描述
TAU与LRP 1在培养的小胶质细胞中的相互作用,并测试这种相互作用刺激LRP 1脱落的假设,
从而激活小胶质细胞并促进炎症虽然我们以前的工作表明,
LRP 1配体在巨噬细胞和小胶质细胞中是保守的,我们必须直接验证这一假设
在小胶质细胞中。TAU对LRP 1脱落、小胶质细胞生理学、细胞信号传导和炎症的影响
将考虑中介表达。将从成年条件基因敲除小鼠中分离小胶质细胞
以确认LRP 1的作用,并测试是否涉及辅助受体。在具体目标2中,我们将研究
小胶质细胞LRP 1对转基因小鼠神经炎症和病理生理学的影响,
表达人TAU的P301 S突变体。这些小鼠产生自发的TAU聚集体,
最终致命的神经炎症在疾病的发病机制中发挥着核心作用。中和
这些小鼠中小胶质细胞中LRP 1的表达将通过与LRP 1缺失的小鼠交配来实现
在小胶质细胞中有活性的启动子系统的控制下。这些研究代表了一个重要的
R 01 HL 136395的扩展,具有产生独立NIH资助赠款的巨大潜力,重点是
AD中神经炎症的全新途径。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
STEVEN L. GONIAS其他文献
STEVEN L. GONIAS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('STEVEN L. GONIAS', 18)}}的其他基金
A novel role for Reelin therapeutics in inflammatory bowel disease
Reelin 疗法在炎症性肠病中的新作用
- 批准号:
10079713 - 财政年份:2020
- 资助金额:
$ 39.5万 - 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
- 批准号:
10358335 - 财政年份:2017
- 资助金额:
$ 39.5万 - 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
- 批准号:
9913997 - 财政年份:2017
- 资助金额:
$ 39.5万 - 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
- 批准号:
10557130 - 财政年份:2017
- 资助金额:
$ 39.5万 - 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
- 批准号:
9285496 - 财政年份:2017
- 资助金额:
$ 39.5万 - 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
- 批准号:
8613477 - 财政年份:2013
- 资助金额:
$ 39.5万 - 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
- 批准号:
8501950 - 财政年份:2013
- 资助金额:
$ 39.5万 - 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
- 批准号:
9023503 - 财政年份:2013
- 资助金额:
$ 39.5万 - 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
- 批准号:
9215655 - 财政年份:2013
- 资助金额:
$ 39.5万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 39.5万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 39.5万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 39.5万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 39.5万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 39.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 39.5万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 39.5万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 39.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 39.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 39.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)