Mechanisms of IgM mediated activation of the complement system
IgM 介导的补体系统激活机制
基本信息
- 批准号:10296558
- 负责人:
- 金额:$ 48.44万
- 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:2021-06-02 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAdoptedAntibodiesAntibody ResponseAntibody-mediated protectionAntigen PresentationAntigensArchitectureAutoimmune DiseasesBindingBiological Response Modifier TherapyCommunicable DiseasesComplementComplement 1qComplement ActivationComplement component C1Complement component C1rComplement component C1sComplexCryoelectron MicroscopyDeuteriumDevelopmentDiseaseElectron MicroscopyFoundationsFutureHeterogeneityHydrogenImmobilizationImmune systemImmunityImmunoglobulin GImmunoglobulin MImmunoglobulinsInfectionLeadMalignant NeoplasmsMapsMass Spectrum AnalysisMediatingMolecularMolecular ConformationMonitorOutcomePharmaceutical PreparationsPhase I Clinical TrialsPolymersPrintingProcessRecombinantsRefractoryResolutionRoentgen RaysScaffolding ProteinStructureSurfaceTechniquesTestingTherapeuticTimeLineantigen bindingarmbasebiophysical toolscancer therapycomplement systemdensitydesignflexibilityfootglycosylationnatural antibodiespathogenrecruitresponsetooltumor
项目摘要
SUMMARY
Immunglobulin µ (IgM) is an evolutionary old class of antibody that is the first antibody
produced in response to an infection. Several IgMs are present as natural antibodies and are vital
for immunity during the early stages of development. Unlike any other class of antibody, a single
copy is sufficient for activating the classical complement system, and several monoclonal IgMs
have shown massive potential for the treatment of cancers. The large size, high degree of
glycosylation, and structural heterogeneity of IgM has rendered them refractory to structural
studies and to date the molecular mechanisms of how antigen binding activates IgM to initiate the
complement cascade remain murky. In contrast, a detailed understanding of the structure and
various interactions of immunoglobulin g (IgG) have been fundamental to their advancement as
the premier molecular platform for biotherapeutics. Accordingly, a similar level of understanding
of IgM will be critical for their development as a new class of biotherapeutics.
This proposal aims to apply structural mass spectrometry techniques, electron microscopy
with complementary structural approaches, and biophysical tools to study the structural changes
within IgM that govern activation of the complement cascade. Various types of IgM-antigen
complexes will be prepared and analyzed using hydrogen/deuterium exchange and X-ray foot
printing with mass spectrometry to track the local structural changes within IgM upon binding
different presentations of antigen (Aim 1). Electron microscopy and small angle X-ray scattering
will be used to visualize and track large-scale structural transitions in the antigen-IgM complexes
(Aim 2). The full combination of techniques will be used to study how IgM recruits and activates
the initial component, C1, of the complement cascade (Aim 3). The molecular mechanisms of
how IgM recognizes antigen and recruits complement will provide a foundation for modulating the
immune system for a new paradigm in biotherapeutics.
摘要
免疫球蛋白(IgM)是一种进化的古老抗体,是第一抗体
为应对感染而产生的。几种免疫球蛋白以天然抗体的形式存在,是至关重要的
在发育的早期阶段获得免疫力。与任何其他类别的抗体不同,单个抗体
复制足以激活经典的补体系统,以及几种单抗IgM
已经显示出治疗癌症的巨大潜力。体型大、程度高
糖基化和IgM的结构异质性使它们难以对结构
抗原结合如何激活IgM启动免疫球蛋白的分子机制研究
补充级联仍不明朗。相比之下,对结构和结构的详细了解
免疫球蛋白g(Igg)的各种相互作用是它们发展为
首屈一指的生物治疗分子平台。因此,类似程度的理解
对于它们作为一类新的生物治疗药物的发展将是至关重要的。
这项提案旨在应用结构质谱学技术、电子显微镜
用互补的结构方法和生物物理工具来研究结构变化
在免疫球蛋白中,控制补体级联的激活。各种类型的IgM抗原
将利用氢/氚交换和X射线脚来制备和分析络合物
用质谱仪打印以跟踪结合时IgM内的局部结构变化
抗原的不同呈现形式(目标1)。电子显微镜与小角X射线散射
将被用于可视化和跟踪抗原-IgM复合体中的大规模结构转变
(目标2)。技术的全面结合将被用来研究IgM是如何招募和激活的
补体级联的初始成分c1(目标3)。其分子机制的研究进展
IgM识别抗原和招募补体的方式将为调节
免疫系统在生物治疗中的新范例。
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 }}
Miklos Guttman其他文献
Miklos Guttman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('Miklos Guttman', 18)}}的其他基金
ThermoFisher Scientific Orbitrap Eclipse with ETD and UVPD
带 ETD 和 UVPD 的 ThermoFisher Scientific Orbitrap Eclipse
- 批准号:
10427682 - 财政年份:2022
- 资助金额:
$ 48.44万 - 项目类别:
Mechanisms of IgM mediated activation of the complement system
IgM 介导的补体系统激活机制
- 批准号:
10416077 - 财政年份:2021
- 资助金额:
$ 48.44万 - 项目类别:
Mechanisms of IgM mediated activation of the complement system
IgM 介导的补体系统激活机制
- 批准号:
10640282 - 财政年份:2021
- 资助金额:
$ 48.44万 - 项目类别:
Multistage LC-MSn for automated glycan isomer assignment of glycopeptides
用于糖肽自动聚糖异构体分配的多级 LC-MSn
- 批准号:
10255170 - 财政年份:2021
- 资助金额:
$ 48.44万 - 项目类别:
Hybrid structural mass spectrometry for rapid site-specific glycan structural elucidation
用于快速位点特异性聚糖结构解析的混合结构质谱法
- 批准号:
10186777 - 财政年份:2018
- 资助金额:
$ 48.44万 - 项目类别:
Investigating the Architecture of HIV Envelope Glycoprotein
研究 HIV 包膜糖蛋白的结构
- 批准号:
8262992 - 财政年份:2012
- 资助金额:
$ 48.44万 - 项目类别:
Investigating the Architecture of HIV Envelope Glycoprotein
研究 HIV 包膜糖蛋白的结构
- 批准号:
8432517 - 财政年份:2012
- 资助金额:
$ 48.44万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 48.44万 - 项目类别:
Research Grant














{{item.name}}会员




