Functionalized Enzyme Treatments for Dual-Targeting of Inflammation in Spinal Cord Injury
功能化酶治疗脊髓损伤炎症的双重靶向
基本信息
- 批准号:10284992
- 负责人:
- 金额:$ 41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnti-Inflammatory AgentsAstrocytesAutoimmuneBindingBinding ProteinsBloodBlood CirculationCarbohydratesCause of DeathCell DeathCellsChronicCicatrixClinicalComplexCuesDepositionDioxygenasesDown-RegulationEngineeringEnzymesExtracellular MatrixFDA approvedFeedbackFormulationGalectin 3GlycosaminoglycansGoalsGrowthHomeostasisHourHuman bodyHydrogelsImmuneImmune responseImmunomodulatorsIndividualInfiltrationInflammationInflammatoryInflammatory ResponseInjectableInjectionsInjuryIntravenousKynurenineLesionLeukocytesLiverMethylprednisoloneMicrogliaModificationMusMuscleNatural regenerationNerveNeuraxisNeurogliaPathologyPathway interactionsPharmaceutical PreparationsPhenotypePolyethylene GlycolsPolysaccharidesProcessProductionPrognosisPropertyProtein EngineeringProteinsPsoriasisRecombinant ProteinsRecombinantsRecovery of FunctionRegimenReperfusion InjuryResearchSiteSkinSpinal CordSpinal Cord LesionsSpinal cord injurySpinal cord injury patientsSteroidsTarget PopulationsTherapeuticTherapeutic EffectTimeTissuesTranslationsTraumaTraumatic CNS injuryTryptophanTryptophan 2,3 DioxygenaseUp-RegulationWorkaxon regenerationcentral nervous system injurycostcytokinedesigndisabilityeffective therapyefficacy testingenzyme therapyglial activationhealinghydrogel scaffoldimmunoregulationimprovedindoleamineinhibitor/antagonistinnovationintravenous administrationmacrophagemonocyteneuroinflammationneutrophilnovelnovel strategiesnovel therapeuticspre-clinical researchpublic health relevanceregenerativeregenerative cellrelating to nervous systemrepairedresponsescaffoldstandard of caresystemic inflammatory responsetissue repairwound healing
项目摘要
PROJECT SUMMARY
Unlike other tissues, such as skin and muscle that are capable of complete tissue remodeling, the central
nervous system (CNS) lacks the ability to properly heal after injury. Instead, CNS wound repair is marked by
sustained glial reactivity and scar tissue deposition, all of which are exacerbated by inflammation. Therapeutic
application of the anti-inflammatory methylprednisolone is the only current treatment option for spinal cord injury
(SCI), however, it only has acute efficacy and does not resolve tissue remodeling or scarring.
This project proposes to investigate idoleamine 2,3-dioxygenase (IDO) as a novel immunomodulatory
therapeutic for SCI. IDO is attractive for its dual targeting ability not only to downregulate pro-inflammatory
responses but also to promote pro-regenerative cell phenotypes, effectively restoring the imbalance of
inflammatory processes after CNS injury. The guiding hypothesis of this research is that IDO will have dual
efficacy in immunomodulation of acute systemic inflammation and mitigation of chronic resident cell activation
and scarring in the spinal cord. Moreover, the project will investigate two innovative, functionalized forms of IDO
for directed targeting of systemic and localized immunomodulation in SCI. First, IDO modified with polyethylene
glycol (PEG) will be used for systemic intravenous administration immediately after SCI. PEG improves protein
stability in blood and prolongs circulation time, making it an ideal candidate for systemic delivery. PEG-IDO will
target circulating leukocytes to modulate early stage inflammation after injury. Secondly, IDO fused with galectin-
3 (Gal3), a glycan binding protein to increase local retention at a tissue target site, will be delivered one week
after injury to evaluate effects on resident cell reactivity, reparative immune cell presence, and tissue scarring.
The rationale for this design is to better harness IDO’s ability to promote reparative mechanisms in immune
cells and glia that are locally present around the lesion site. Co-administration of IDO-Gal3 with key compounds
that direct production of neuroprotective metabolites by resident glia (i.e., KMO inhibitors) will further enhance
therapeutic effects of localized IDO. Together, this combination will be delivered within a novel, pro-regenerative
decellularized neural scaffold to synergistically mitigate neuroinflammation.
Overall, the dual immunomodulation potential of IDO provides a new perspective for anti-inflammatory drug
administration for CNS injury. The proposed work will demonstrate merit for the individual novel approaches with
PEG-IDO and IDO-Gal3 for cell-specific targeting. The long-term goal is to use this mechanistic understanding
as a first step in research efforts to develop more effective combination strategies for CNS repair.
项目摘要
与能够完全组织重塑的其他组织(例如皮肤和肌肉)不同,中枢神经系统是一种神经系统。
神经系统(CNS)在损伤后缺乏适当愈合的能力。相反,CNS伤口修复的标志是
持续的神经胶质反应和瘢痕组织沉积,所有这些都因炎症而加剧。治疗
应用抗炎的甲基强的松龙是目前脊髓损伤的唯一治疗选择
(SCI)然而,它仅具有急性功效,并且不能解决组织重塑或瘢痕形成。
本项目拟研究吲哚胺2,3-双加氧酶(IDO)作为一种新型的免疫调节剂,
治疗SCI。IDO的吸引力在于其双重靶向能力,不仅下调促炎性细胞因子,
反应,但也促进促再生细胞表型,有效地恢复不平衡,
CNS损伤后的炎症过程。本研究的指导假设是,IDO将具有双重
在急性全身性炎症免疫调节和慢性驻留细胞活化减轻中的功效
和脊髓上的疤痕此外,该项目还将研究两种创新的功能化IDO形式
用于SCI中系统性和局部免疫调节的定向靶向。首先,用聚乙烯改性的IDO
乙二醇(PEG)将用于SCI后立即全身静脉给药。PEG改善蛋白质
在血液中的稳定性和延长循环时间,使其成为全身递送的理想候选物。PEG-IDO将
靶向循环白细胞以调节损伤后早期炎症。其次,IDO与半乳糖凝集素融合,
3(Gal 3),一种聚糖结合蛋白,以增加在组织靶位点的局部保留,将在一周内递送
以评估对驻留细胞反应性、修复性免疫细胞存在和组织瘢痕形成的影响。
这种设计的基本原理是更好地利用IDO促进免疫系统中修复机制的能力。
细胞和神经胶质,局部存在于病变部位周围。IDO-Gal 3与关键化合物的共同施用
其指导驻留神经胶质细胞产生神经保护性代谢物(即,KMO抑制剂)将进一步增强
局部IDO的治疗效果。总之,这种组合将在一种新颖的,亲再生的
脱细胞神经支架以协同减轻神经炎症。
总体而言,IDO的双重免疫调节潜力为抗炎药物提供了新的视角
用于CNS损伤的施用。拟议的工作将证明个别新方法的优点,
PEG-IDO和IDO-Gal 3用于细胞特异性靶向。长期目标是利用这种机械的理解
作为研究工作的第一步,以开发更有效的中枢神经系统修复组合策略。
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)
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Benjamin George Keselowsky其他文献
Benjamin George Keselowsky的其他文献
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{{ truncateString('Benjamin George Keselowsky', 18)}}的其他基金
Directing Tryptophan Immunometabolism to Ameliorate Liver Ischemic-Reperfusion Injury
指导色氨酸免疫代谢改善肝脏缺血再灌注损伤
- 批准号:
10595020 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Directing Tryptophan Immunometabolism to Ameliorate Liver Ischemic-Reperfusion Injury
指导色氨酸免疫代谢改善肝脏缺血再灌注损伤
- 批准号:
10444213 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Diversity Supplement: Directing Tryptophan Immunometabolism to Ameliorate Liver Ischemic-Reperfusion Injury
多样性补充剂:引导色氨酸免疫代谢改善肝脏缺血再灌注损伤
- 批准号:
10632561 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Tissue-Targeted Enzyme for Localized Tryptophan Catabolism to Direct Subcutaneous and Oral Mucosal Inflammatory Responses
用于局部色氨酸分解代谢的组织靶向酶以指导皮下和口腔粘膜炎症反应
- 批准号:
9752509 - 财政年份:2017
- 资助金额:
$ 41万 - 项目类别:
Tissue-Targeted Enzyme for Localized Tryptophan Catabolism to Direct Subcutaneous and Oral Mucosal Inflammatory Responses
用于局部色氨酸分解代谢的组织靶向酶以指导皮下和口腔粘膜炎症反应
- 批准号:
9403768 - 财政年份:2017
- 资助金额:
$ 41万 - 项目类别:
Biomaterial Delivery System for Type 1 Diabetes Vaccine
1 型糖尿病疫苗的生物材料输送系统
- 批准号:
9285796 - 财政年份:2014
- 资助金额:
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Biomaterial Delivery System for Type 1 Diabetes Vaccine
1 型糖尿病疫苗的生物材料输送系统
- 批准号:
8761784 - 财政年份:2014
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Dendritic Cell-Targeting Microparticles for Subcellularly-Targeted Delivery of In
用于亚细胞靶向递送 In 的树突状细胞靶向微粒
- 批准号:
8707719 - 财政年份:2012
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$ 41万 - 项目类别:
Dendritic Cell-Targeting Microparticles for Subcellularly-Targeted Delivery of In
用于亚细胞靶向递送 In 的树突状细胞靶向微粒
- 批准号:
9041572 - 财政年份:2012
- 资助金额:
$ 41万 - 项目类别:
Dendritic Cell-Targeting Microparticles for Subcellularly-Targeted Delivery of In
用于亚细胞靶向递送 In 的树突状细胞靶向微粒
- 批准号:
8821609 - 财政年份:2012
- 资助金额:
$ 41万 - 项目类别:
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