Regulation of Peripheral Neuropathic Pain by B Cells

B 细胞对周围神经病理性疼痛的调节

基本信息

  • 批准号:
    10588250
  • 负责人:
  • 金额:
    $ 62.66万
  • 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:
    2022-03-15 至 2027-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Effective treatments are elusive for the majority of patients with neuropathic pain, which is reflective of the incomplete knowledge of the underlying mechanisms. Our proposal will advance mechanistic understanding of peripheral neuropathic pain maintenance by investigating the differentiation and function of B cells after peripheral nerve injury. Our long-term goal is to harness the disease-modifying potential of neuroimmune signaling to treat neuropathic pain. As a step toward achieving this goal, the overall objective of this application is to discover if and how B cells cause neuropathic pain after peripheral nerve injury. Our central hypothesis is that peripheral nerve injury induces differentiation of B cells into plasma cells. The plasma cells secrete autoantibodies that form complexes with autoantigens which maintain neuropathic pain by signaling through the activating Fc gamma receptor (FcγR) subtypes (I, III, IV) along the pain neuraxis. We propose that insufficient efferocytosis (deficient non-inflammatory clearance of apoptotic cells, leading to release of Danger Associated Molecular Patterns (DAMPs)) at the site of nerve injury, triggers autoimmune B cell differentiation. This hypothesis is based on strong evidence that plasma cells are pro-nociceptive, as we show that either constitutive deficiency or pharmacological depletion of differentiating B cells protects male and female mice from neuropathic pain. Our data also reveal that insufficient efferocytosis leads to B cell differentiation, as pharmacological stimulation of efferocytosis at the time of peripheral nerve injury reduces immunoglobulin G (IgG) deposits in the spinal dorsal horn. The rationale for testing our hypothesis is that deciphering this previously overlooked adaptive immune response to peripheral nerve injury will reveal new and tractable therapeutic targets for neuropathic pain. To accomplish the overall objective of this application, we will test the central hypothesis in a mouse model of peripheral nerve injury across the following specific aims: 1) Define the function of B cell differentiation after peripheral nerve injury. Validation studies will be performed in a piglet model of peripheral injury, and in biological samples obtained from patients with lumbar radiculopathy; 2) Identify whether FcγR signaling maintains neuropathic pain; and, 3) Determine whether insufficient efferocytosis induces B cell differentiation leading to neuropathic pain. The proposed studies take a multidisciplinary approach, including pharmacologic and genetic manipulations, flow cytometry, in situ hybridization, adoptive transfer, and assessment of evoked and operant pain behaviors. As efferocytosis and downstream plasma cell differentiation have not been previously implicated in traumatic neuropathic pain, our proposal is highly innovative and is expected to expand our paradigm for neuroimmune regulation of peripheral neuropathic pain. The results will have significant impact on the treatment of peripheral neuropathic pain by revealing new sites for therapeutic intervention.
项目摘要 对于大多数患有神经性疼痛的患者来说,有效的治疗是难以实现的,这反映了神经性疼痛的严重性。 对潜在机制的了解不完整。我们的建议将促进机械理解, 外周神经病理性疼痛的维持,通过研究B细胞的分化和功能, 周围神经损伤我们的长期目标是利用神经免疫调节疾病的潜力, 信号传导来治疗神经性疼痛。作为实现这一目标的一步,本申请的总体目标是 是发现B细胞是否以及如何在周围神经损伤后引起神经性疼痛。我们的核心假设是 外周神经损伤诱导B细胞分化为浆细胞。浆细胞分泌 与自身抗原形成复合物的自身抗体,其通过经由神经元的信号传导维持神经性疼痛。 沿着疼痛神经轴激活Fc γ受体(FcγR)亚型(I、III、IV)。我们建议, 红细胞增多症(凋亡细胞的非炎性清除不足,导致释放危险相关的 分子模式(DAMP))在神经损伤部位触发自身免疫性B细胞分化。这 这一假设是基于强有力的证据,即浆细胞是亲伤害感受的,因为我们表明,无论是组成性的, 分化中B细胞的缺乏或药理学耗竭保护雄性和雌性小鼠免受神经病理性损伤 痛苦我们的数据还表明,不充分的红细胞导致B细胞分化,作为药理学 周围神经损伤时刺激细胞发热减少了免疫球蛋白G(IgG)在脑中的沉积 脊髓背角测试我们假设的基本原理是, 对周围神经损伤免疫应答将揭示神经病理性损伤的新的和易处理的治疗靶点 痛苦为了实现本申请的总体目标,我们将在小鼠模型中检验中心假设 周围神经损伤的研究有以下具体目标:1)定义损伤后B细胞分化的功能 周围神经损伤将在外周损伤的仔猪模型和生物学模型中进行验证研究。 从腰椎神经根病患者中获得的样本; 2)确定FcγR信号传导是否维持 神经性疼痛;和,3)确定红细胞增多症不足是否诱导B细胞分化,导致 神经性疼痛拟议的研究采取多学科方法,包括药理学和遗传学 操作,流式细胞术,原位杂交,过继转移,以及诱发和操作性 疼痛行为由于胞浆细胞增多和下游浆细胞分化以前没有涉及 在创伤性神经病理性疼痛中,我们的建议是高度创新的,并有望扩展我们的范式, 外周神经病理性疼痛的神经免疫调节。结果将对治疗产生重大影响 通过揭示新的治疗干预位点来研究周围神经性疼痛。

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 }}

Peter M Grace其他文献

Peter M Grace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('Peter M Grace', 18)}}的其他基金

Regulation of Peripheral Neuropathic Pain by B Cells
B 细胞对周围神经病理性疼痛的调节
  • 批准号:
    10417954
  • 财政年份:
    2022
  • 资助金额:
    $ 62.66万
  • 项目类别:
PQ12 Targeting HDAC6 for Chemotherapy-Induced Neuropathy and Chemobrain
PQ12 靶向 HDAC6 治疗化疗引起的神经病变和化疗脑
  • 批准号:
    10376221
  • 财政年份:
    2018
  • 资助金额:
    $ 62.66万
  • 项目类别:
PQ12 Targeting HDAC6 for Chemotherapy-Induced Neuropathy and Chemobrain
PQ12 靶向 HDAC6 治疗化疗引起的神经病变和化疗脑
  • 批准号:
    10685944
  • 财政年份:
    2018
  • 资助金额:
    $ 62.66万
  • 项目类别:

相似海外基金

University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
  • 批准号:
    10073243
  • 财政年份:
    2024
  • 资助金额:
    $ 62.66万
  • 项目类别:
    Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
  • 批准号:
    10752129
  • 财政年份:
    2024
  • 资助金额:
    $ 62.66万
  • 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
  • 批准号:
    2339201
  • 财政年份:
    2024
  • 资助金额:
    $ 62.66万
  • 项目类别:
    Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
  • 批准号:
    MR/Y008693/1
  • 财政年份:
    2024
  • 资助金额:
    $ 62.66万
  • 项目类别:
    Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
  • 批准号:
    10076445
  • 财政年份:
    2023
  • 资助金额:
    $ 62.66万
  • 项目类别:
    Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
  • 批准号:
    23K14783
  • 财政年份:
    2023
  • 资助金额:
    $ 62.66万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
  • 批准号:
    23KJ0394
  • 财政年份:
    2023
  • 资助金额:
    $ 62.66万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
  • 批准号:
    10639161
  • 财政年份:
    2023
  • 资助金额:
    $ 62.66万
  • 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
  • 批准号:
    10752441
  • 财政年份:
    2023
  • 资助金额:
    $ 62.66万
  • 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
  • 批准号:
    10867639
  • 财政年份:
    2023
  • 资助金额:
    $ 62.66万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了