Cell-directed gene therapy for pain recovery after surgery and inflammation
用于手术和炎症后疼痛恢复的细胞定向基因疗法
基本信息
- 批准号:10546458
- 负责人:
- 金额:$ 45.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-15 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcute PainAddressAnti-Inflammatory AgentsArthritisAttentionBehaviorBehavior assessmentBehavioralBioinformaticsBiological AssayCellsChronicChronic inflammatory painClinicalComplementary DNAComplexCritical PathwaysDataDevelopmentDimensionsDisease ProgressionDoseDose LimitingDrug abuseFreund&aposs AdjuvantGene ExpressionGenesGenetic TranscriptionHumanImmune responseImmune systemImmunobiologyImmunologicsInfiltrationInflammationInflammation MediatorsInflammatoryInjuryInterleukin-1 betaInterventionKneeLightLinkMacrophageMeasuresMechanicsMediatorModelingMolecularMorphineMuscleNanotechnologyNucleic AcidsOperative Surgical ProceduresOpioidOutcomePainPain managementPatientsPeripheralPharmaceutical PreparationsPhenotypePlasmidsPolyethyleneiminePositioning AttributePostoperative PainProcessProductionRattusRecoveryRecovery of FunctionResearchResolutionSignal PathwaySignal TransductionSkinSkin TissueSmall Interfering RNASpeedSurgical ModelsSurgical incisionsTNF geneTechnologyTestingTherapeuticTissuesTractionTraumaWeight-Bearing stateaddictionchronic painchronic pain managementclinically relevantcytokinedesigngain of functiongene inductiongene therapygenetic signaturegenome-widehigh riskhuman dataimprovedinflammatory paininjuredinnovationinsightknock-downloss of functionmultidisciplinarynanoparticlenon-opioid analgesicnovelopioid abuseopioid epidemicopioid sparingoverexpressionpain behaviorpain modelpain reductionpostoperative recoverypreventprogramsresponseside effectsingle-cell RNA sequencingsurgical paintherapeutic targettissue repairtooltranscriptome sequencingtranscriptomicstranslational potentialwoundwound healing
项目摘要
Summary
We have recently discovered macrophage ED2/CD163 gene overexpression as a novel and safe pain
therapeutic target in the local peripheral immune system in a major surgery rat model. We propose to develop a
cell-directed gene therapy that would correct the underlying local immunological cause of pain resulting from
inflammatory processes, specifically in sub-chronic postoperative pain or inflammatory conditions. Through
unbiased genome-wide transcriptomic analyses in human primary macrophages we identified that ED2/CD163
gene induction modulates tumor necrosis factor alpha (TNFa) and interleukin (IL)-1 beta (IL-1b). CD163
overexpression using a clinically tested nanoparticle designed to target macrophages promoted a more rapid
wound healing in 3D human organotypic skin tissues and prevented sub-chronic postoperative pain behaviors
and reduced local TNFa and IL-1b in rats with skin-muscle incision and retraction (SMIR) surgery. We
hypothesize that ED2/CD163 in macrophages is a safe target for the treatment of inflammatory pain with
opioid sparing effects. We propose a multidimensional research plan including, 1) a sub-chronic surgical pain
model, the SMIR surgery, and a knee inflammatory mode, the Complete Freund Adjuvant (CFA)-induced knee
arthritis; 2) ED2/CD163 gain and loss of function using macrophage-directed nanotechnology; 3) novel, clinically
relevant, and complex operant pain-related behaviors; 4) cellular/molecular, tissue, and transcriptomic outcomes
for mechanistic target engagement; and 5) studies for ED2/CD163’s effects on opioid requirements. We will
implement our plan through these specific aims: 1) Determine that macrophage specific ED2/CD163 gene
induction effectively promotes resolution of inflammatory pain. A mannosilated polyethyleneimine
nanoparticles (Man-PEI) designed to deliver nucleic acids specifically to macrophages will be used to conduct
ED2/CD163 gain (overexpression) or loss (knock down) of function. We will assess classic behaviors (von Frey
and weight bearing), and novel complex and clinically relevant functional activity and attention-related behaviors
developed and validated by our team. 2) Define ED2/CD163 target engagement, i.e. ED2/CD163 as a
signaling driver that dictates the dynamics of macrophage phenotype change and cellular reprogramming
in inflammatory pain. TNFa and IL-1b will be measured as downstream target engagement. Also, we will use
single-cell RNAseq (scRNAseq), cluster, and phenotype trajectory analysis to define how ED2/CD163 impacts
gene expression programs in macrophages infiltrating the inflamed tissue. 3) Establish that macrophage
ED2/CD163 gene induction results in opioid-sparing effects in surgical and inflammatory pain. We will
construct dose responses of morphin in rats with SMIR or arthritis and ED2/CD163 overexpression to measure
opioid-sparing effects. Our project will establish ED2/CD163 as a cell-directed gene therapy for postsurgical pain
that will reduce opioid requirements and disinter how it influences immune responses and inflammatory pain
recovery. Our multidisciplinary team is uniquely equipped to successfully complete these studies.
总结
我们最近发现巨噬细胞ED 2/CD 163基因过表达作为一种新的和安全的疼痛
在大手术大鼠模型中局部外周免疫系统中的治疗靶点。我们建议发展一个
细胞导向的基因治疗,将纠正潜在的局部免疫性疼痛的原因,
炎症过程,特别是在亚慢性术后疼痛或炎症状况。通过
在人原代巨噬细胞中进行的无偏全基因组转录组分析中,我们确定ED 2/CD 163
基因诱导调节肿瘤坏死因子α(TNF α)和白细胞介素(IL)-1 β(IL-1b)。CD163
使用临床测试的旨在靶向巨噬细胞的纳米颗粒进行过表达,可以促进细胞更快地表达。
3D人体器官型皮肤组织的伤口愈合并预防亚慢性术后疼痛行为
并减少皮肤肌肉切开牵开术(SMIR)大鼠局部TNF α和IL-1b。我们
假设巨噬细胞中ED 2/CD 163是治疗炎性疼痛的安全靶点,
阿片类药物的节省作用。我们提出了一个多维的研究计划,包括:1)亚慢性手术疼痛
模型,SMIR手术,和膝关节炎症模型,完全弗氏佐剂(CFA)诱导的膝关节
关节炎; 2)使用巨噬细胞定向纳米技术的ED 2/CD 163功能获得和丧失; 3)新的,临床上
相关和复杂的操作性疼痛相关行为; 4)细胞/分子、组织和转录组学结果
5)ED 2/CD 163对阿片类药物需求的影响的研究。我们将
通过以下具体目标实施我们的计划:1)确定巨噬细胞特异性ED 2/CD 163基因
诱导有效地促进炎性疼痛的消退。一种甘露糖化聚乙烯亚胺,
设计用于将核酸特异性递送至巨噬细胞的纳米颗粒(Man-PEI)将用于进行
ED 2/CD 163功能获得(过表达)或丧失(敲低)。我们将评估典型的行为(冯弗雷
和负重),以及新的复杂的和临床相关的功能活动和注意力相关的行为
由我们的团队开发和验证。2)定义ED 2/CD 163目标接合,即ED 2/CD 163作为
决定巨噬细胞表型变化和细胞重编程动力学的信号驱动因子
炎症性疼痛。将测量TNFa和IL-1b作为下游靶点接合。此外,我们将使用
单细胞RNAseq(scRNAseq)、聚类和表型轨迹分析,以确定ED 2/CD 163如何影响
浸润发炎组织的巨噬细胞中的基因表达程序。3)建立巨噬细胞
ED 2/CD 163基因诱导导致手术和炎性疼痛中的阿片样物质节省效应我们将
构建吗啡在SMIR或关节炎和ED 2/CD 163过表达大鼠中的剂量反应,以测量
阿片类药物的作用我们的项目将建立ED 2/CD 163作为手术后疼痛的细胞定向基因治疗
这将减少阿片类药物的需求,并揭示它如何影响免疫反应和炎症疼痛
复苏我们的多学科团队具有独特的能力来成功完成这些研究。
项目成果
期刊论文数量(0)
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THOMAS JEFFREY MARTIN其他文献
THOMAS JEFFREY MARTIN的其他文献
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{{ truncateString('THOMAS JEFFREY MARTIN', 18)}}的其他基金
Central oxytocin mechanisms of pain recovery following nerve injury
神经损伤后疼痛恢复的中枢催产素机制
- 批准号:
10609950 - 财政年份:2022
- 资助金额:
$ 45.9万 - 项目类别:
Central oxytocin mechanisms of pain recovery following nerve injury
神经损伤后疼痛恢复的中枢催产素机制
- 批准号:
10332264 - 财政年份:2022
- 资助金额:
$ 45.9万 - 项目类别:
Cell-directed gene therapy for pain recovery after surgery and inflammation
用于手术和炎症后疼痛恢复的细胞定向基因疗法
- 批准号:
10390750 - 财政年份:2022
- 资助金额:
$ 45.9万 - 项目类别:
The Monogamous Prairie Vole: A Model for the Study of Social Behavior and Pain
一夫一妻制的草原田鼠:研究社会行为和疼痛的模型
- 批准号:
8929319 - 财政年份:2014
- 资助金额:
$ 45.9万 - 项目类别:
The Monogamous Prairie Vole: A Model for the Study of Social Behavior and Pain
一夫一妻制的草原田鼠:研究社会行为和疼痛的模型
- 批准号:
8823884 - 财政年份:2014
- 资助金额:
$ 45.9万 - 项目类别:
Behavioral effects of deep brain stimulation in rats with chronic pain
深部脑刺激对慢性疼痛大鼠的行为影响
- 批准号:
8310618 - 财政年份:2012
- 资助金额:
$ 45.9万 - 项目类别:
Behavioral effects of deep brain stimulation in rats with chronic pain
深部脑刺激对慢性疼痛大鼠的行为影响
- 批准号:
8472548 - 财政年份:2012
- 资助金额:
$ 45.9万 - 项目类别:
Role of the Amygdala in Opioid Self-administration in Rats with Chronic Pain.
杏仁核在慢性疼痛大鼠阿片类药物自我给药中的作用。
- 批准号:
7460617 - 财政年份:2006
- 资助金额:
$ 45.9万 - 项目类别:
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