Development of a Treatment for Eosinophil-Mediated Allergic Inflammatory Diseases Utilizing a Neutralizing Agent Targeting Eosinophil Granule Major Basic Protein
利用针对嗜酸性粒细胞颗粒主要碱性蛋白的中和剂开发治疗嗜酸性粒细胞介导的过敏性炎症疾病的方法
基本信息
- 批准号:10257909
- 负责人:
- 金额:$ 29.98万
- 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:2021-05-07 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAllergicAllergic inflammationAmino Acid SequenceAsthmaAvidityBacteriaBasophilsBindingBiologicalBlood CirculationCationsCellsCharacteristicsChemicalsChronicComplementary DNACytoplasmic GranulesDepositionDevelopmentDiseaseEmbryoEosinophil Granule ProteinsEosinophil cationic proteinEvaluationFutureGastrointestinal DiseasesGlycosaminoglycansGoalsHelminthsHistamine ReleaseHumanImmuneInflammationInflammatoryK-562K562 CellsLeadLeukocytesLinkMeasurementMeasuresMediatingMethodsModelingMolecularMolecular WeightNeutralization TestsParasitesPatientsPeptidesPhasePolysaccharidesPopulationProcessProductionProteinsRattusResearchSinusSmall Business Innovation Research GrantStructureStructure of respiratory epitheliumSurface Plasmon ResonanceTestingTissuesToxic effectToxinanalogchronic rhinosinusitisdesigneosinophileosinophil peroxidaseexperimental studyglycosylationhuman diseaseimprovedin vitro Modelin vivo evaluationkidney cellmast cellmicrobialmutantneoplastic cellperipheral bloodsuccesstargeted agent
项目摘要
ABSTRACT
The eosinophil is a peripheral blood leukocyte containing an abundance of cytoplasmic granules, rich in cationic
protein toxins. Among these, the most abundant on a molar basis is the major basic protein-1, eMBP1. eMBP1
kills helminths, bacteria, and numerous cells, such as respiratory epithelium, but also activates cells, including
basophils and mast cells. Studies of human diseases show that eMBP1 is present in secretions from patients
with eosinophil-mediated diseases, including asthma, chronic rhinosinusitis, and gastrointestinal diseases, and
it is deposited on damaged targets. These studies show that the eosinophil mediates its damage to parasites
and tissues by discharging its toxin rich granules onto microbial targets and tissues. eMBP1 is synthesized as
a precursor, pro-eMBP1, composed of eMBP1 and a remarkably acidic pro-piece sequence. Developing
eosinophils synthesize pro-eMBP1, and the pro-piece is removed during granule maturation. Analyses of pro-
piece in different models show that it can neutralize the toxic eMBP1 effect and also the toxicity of the eosinophil
cationic protein (ECP). This project proposes that neutralization of eMBP1 can be a treatment to mitigate tissue
damage in eosinophil-related diseases. It will develop a pro-piece product for treatment of eosinophil-mediated
diseases by neutralization of eMBP1 and other granule toxins. Currently, no therapies for these diseases
address the neutralization of granule proteins.
In this project, the pro-piece will be expressed and associated glycans will be modified to identify the optimal
form of the molecule for binding to and neutralizing eMBP1. These tests will determine whether glycosylation of
pro-piece importantly alters its binding to eMBP1 by analyzing whether N- or O- glycans and the
glycosaminoglycan at S62 modify its activities. The project will identify the most important pro-piece regions for
binding eMBP1 and neutralizing it by creating overlapping peptides and creating mutants with increased amino
acid sequences characteristic of active regions. Evaluation of the pro-piece panel for binding to and inhibiting
eMBP1 will be evaluated here in several in vitro models. The goal of this project is to identify an active form of
the pro-piece with optimal inhibition effects on eMBP1 and other granule toxic proteins. This form will be further
investigated and developed in future projects.
摘要
嗜酸性粒细胞是一种外周血白细胞,含有丰富的细胞质颗粒,富含阳离子型
蛋白质毒素其中,最丰富的摩尔基础上是主要的碱性蛋白-1,eMBP 1。eMBP 1
杀死蠕虫,细菌和许多细胞,如呼吸道上皮细胞,但也激活细胞,包括
嗜碱性粒细胞和肥大细胞。对人类疾病的研究表明,eMBP 1存在于患者的分泌物中
嗜酸性粒细胞介导的疾病,包括哮喘、慢性鼻窦炎和胃肠道疾病,
它会沉积在受损的目标上。这些研究表明,嗜酸性粒细胞介导其损害寄生虫
通过将其富含毒素的颗粒释放到微生物靶点和组织上而释放到组织中。eMBP 1的合成如下:
前体pro-eMBP 1,由eMBP 1和显著酸性的前片段序列组成。发展中
嗜酸性粒细胞合成pro-eMBP 1,并且在颗粒成熟过程中去除pro-piece。亲分析
在不同模型中的结果表明,它可以中和毒性eMBP 1效应以及嗜酸性粒细胞的毒性
阳离子蛋白(ECP)。该项目提出,eMBP 1的中和可以是一种治疗,以减轻组织
嗜酸性粒细胞相关疾病的损害。它将开发一种用于治疗嗜酸性粒细胞介导的
通过中和eMBP 1和其他颗粒毒素来预防疾病。目前,这些疾病的治疗方法
解决颗粒蛋白的中和。
在这个项目中,前片将被表达,相关的聚糖将被修饰,以确定最佳的
用于结合和中和eMBP 1的分子形式。这些测试将确定糖基化是否
前片段通过分析N-或O-聚糖和糖基化蛋白是否与eMBP 1结合而重要地改变其与eMBP 1的结合。
在S62处的糖胺聚糖改变其活性。该项目将确定最重要的专业领域,
结合eMBP 1并通过产生重叠肽和产生具有增加的氨基酸的突变体来中和它
酸性序列是活动区的特征。评价前片段组的结合和抑制
eMBP 1将在几种体外模型中进行评价。该项目的目标是确定一种活跃的形式,
对eMBP 1等颗粒毒性蛋白抑制效果最佳的原片段。这种形式将进一步
在未来的项目中进行研究和开发。
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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Gerald J Gleich其他文献
Lidocaine may inhibit interleukin-5-induced signal transduction by blocking protein kinase C activity
- DOI:
10.1016/s0091-6749(02)82134-0 - 发表时间:
2002-01-01 - 期刊:
- 影响因子:
- 作者:
Jennifer L Bankers-Fulbright;Gail M Kephart;Matthew P Abdel;Patricia L Caffes;Kara Hurlihy;Gerald J Gleich - 通讯作者:
Gerald J Gleich
VENOM IMMUNOTHERAPY FOR HONEYBEE STING-SENSITIVE PERSONS
针对对蜜蜂蜇刺敏感人群的毒液免疫疗法
- DOI:
10.1203/00006450-197704000-00761 - 发表时间:
1977-04-01 - 期刊:
- 影响因子:3.100
- 作者:
John W Yunginger;Barry R Paull;Gerald J Gleich;G S Gilchrist - 通讯作者:
G S Gilchrist
Gerald J Gleich的其他文献
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{{ truncateString('Gerald J Gleich', 18)}}的其他基金
Development of a Treatment for Eosinophil-Mediated Allergic Inflammatory Diseases Utilizing a Neutralizing Agent Targeting Eosinophil Granule Major Basic Protein
利用针对嗜酸性粒细胞颗粒主要碱性蛋白的中和剂开发治疗嗜酸性粒细胞介导的过敏性炎症疾病的方法
- 批准号:
10401936 - 财政年份:2021
- 资助金额:
$ 29.98万 - 项目类别:
Novel, Non-InvasiveImaging of Eosinophil-Related Inflammation Throughout the Esophagus in Patients withEosinophilic Esophagitis
嗜酸性粒细胞性食管炎患者食管内嗜酸性粒细胞相关炎症的新型非侵入性成像
- 批准号:
10017684 - 财政年份:2020
- 资助金额:
$ 29.98万 - 项目类别:
STANDARD VALUES OF EOSINOPHIL-RELATED PARAMETERS FOR DATA COMPARISON
用于数据比较的嗜酸性粒细胞相关参数的标准值
- 批准号:
7718523 - 财政年份:2008
- 资助金额:
$ 29.98万 - 项目类别:
CLINICAL TRIAL: ICATIBANT FOR THE TREATMENT OF HEREDITARY ANGIOEDEMA
临床试验:艾替班特治疗遗传性血管性水肿
- 批准号:
7718517 - 财政年份:2008
- 资助金额:
$ 29.98万 - 项目类别:
THE HYPEREOSINOPHILIC SYNDROMES AND MEPOLIZUMAB
高嗜酸性粒细胞综合征和美泊利珠单抗
- 批准号:
7718504 - 财政年份:2008
- 资助金额:
$ 29.98万 - 项目类别:
ICATIBANT FOR THE TREATMENT OF HEREDITARY ANGIOEDEMA
Icatibant 用于治疗遗传性血管性水肿
- 批准号:
7604975 - 财政年份:2007
- 资助金额:
$ 29.98万 - 项目类别:
STANDARD VALUES OF EOSINOPHIL-RELATED PARAMETERS FOR DATA COMPARISON
用于数据比较的嗜酸性粒细胞相关参数的标准值
- 批准号:
7604980 - 财政年份:2007
- 资助金额:
$ 29.98万 - 项目类别:
THE HYPEREOSINOPHILIC SYNDROMES AND MEPOLIZUMAB
高嗜酸性粒细胞综合征和美泊利珠单抗
- 批准号:
7604962 - 财政年份:2007
- 资助金额:
$ 29.98万 - 项目类别:
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