Targeting pathologic macrophage activation through inhibition of MyD88 to attenuate laryngotracheal stenosis
通过抑制 MyD88 靶向病理性巨噬细胞激活以减轻喉气管狭窄
基本信息
- 批准号:10644555
- 负责人:
- 金额:$ 19.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AdultAttenuatedAutomobile DrivingBiological Response ModifiersBiopsyBypassCD4 Positive T LymphocytesCellsCollagenCommunication impairmentCritical IllnessCritical PathwaysDataDevelopmentDiseaseDysphoniaDyspneaExcisionExperimental DesignsFibrosisFlow CytometryFoundationsGene ExpressionGoalsHistologicHumanIatrogenesisImmuneImmune TargetingImmune responseImmunologyImmunophenotypingInflammationInflammatory InfiltrateInjuryInterleukin-1 betaInterventionIntratracheal IntubationIntubationInvestigationKnowledgeLaboratoriesLamina PropriaLaryngeal DiseasesLarynxLeadLifeMacrophageMacrophage ActivationMediatingMedicalMentorsModelingMolecularMucous MembraneMusOperative Surgical ProceduresPathogenesisPathologicPathway interactionsPatientsPatternPhenotypePhysiologicalPopulationProteinsRegulatory PathwayResearchResearch TrainingResectedRoleS100A8 geneSecondary toSerumSignal PathwaySignal TransductionSourceStenosisSubglottis structureTLR4 geneTherapeutic InterventionTissuesToll-like receptorsTracheaTracheostomy procedureTransgenic Organismsbiomarker developmentcandidate markercareercytokineexperiencegenetic regulatory proteinimprovedmouse modelpathogenpreventprotein expressionreceptorsingle-cell RNA sequencingskillstargeted treatmenttreatment strategywound healing
项目摘要
Project Summary:
Laryngotracheal Stenosis (LTS) is the pathologic narrowing of the larynx, subglottis, and trachea
secondary to mucosal injury from prolonged intubation. This narrowing leads to dyspnea, dysphonia, and can
rapidly progress to airway compromise. Therapeutic interventions for the management of LTS are limited to
serial dilation, tracheal resection, or permanent tracheostomy which further impairs communication. Medical
therapies for LTS are limited by our poor understanding of LTS pathogenesis. Improved understanding of the
mechanisms promoting LTS is needed to improve treatment of this debilitating disease.
Previous investigation has revealed that an intact immune response is critical to the development of LTS.
Characterization of the immune response in LTS has demonstrated increased populations of CD4+ T-cells and
macrophages. Preliminary studies in a murine LTS model reveal that depletion of the macrophage population
attenuates LTS fibrosis, implicating their pathologic role. However, the local immune mediators and cell signaling
pathways promoting pathologic macrophages in LTS are unknown.
Macrophage activation is regulated through stimulation of Toll-like receptors (TLRs). TLRs are highly
conserved receptors recognizing Pathogen or Damage Associated Molecular Patterns (PAMPs/DAMPs) and
lead to downstream activation of regulatory proteins controlling phenotype. Using single cell RNA sequencing
the PI has demonstrates increased expression of the TLR4-MyD88 signaling pathway in LTS macrophages.
Furthermore, we have identified increased expression of the DAMP S100A8/A9 in LTS tissue. S100A8/A9 is a
known activator of TLR4-MyD88 signaling, and worsens fibrosis in our murine LTS model. These findings
indicate that TLR4-MyD88 signaling pathways in macrophages may be critical to LTS pathogenesis. However,
the relationship between S100A8/A9, TLR4-MyD88 signaling, and pathologic macrophages has not been
explored in LTS or other fibrotic diseases, and may represent a critical signaling axis driving pathologic fibrosis.
For this study, we will elucidate the signaling networks promoting pathologic macrophages in laryngotracheal
stenosis. In Aim 1 we will assess effect of S100A8/A9 on macrophage phenotype and function in a murine LTS
model, establish that S100A8/A9s profibrotic effect is mediated by macrophages, and identify the key sources
of pathologic S100A8/A9 in human LTS and a murine model. In Aim 2, we will demonstrate the critical role of
TLR4-MyD88 signaling in promoting pathologic macrophages in LTS, and elucidate the role of IL1β in promoting
LTS fibrosis. Finally, in Aim 3 we will assess S100A8/A9 as a candidate biomarker for the development of
laryngotracheal stenosis in patients who have had prolonged intubation. Collectively, this application will lead to
an in-depth understanding of the cell signaling networks promoting dysregulated macrophage mediated
inflammation and subsequent fibrosis in LTS. The identification of key regulatory pathways promoting pathologic
macrophages in LTS will serve as the foundation for targeted treatment strategies that attenuate fibrosis.
项目概要:
喉气管狭窄(LTS)是喉、声门下和气管的病理性狭窄
继发于长时间插管造成的粘膜损伤。这种狭窄会导致呼吸困难、发声困难,并且可能
迅速发展为气道损伤。用于管理LTS的治疗干预措施仅限于
连续扩张、气管切除或永久性气管造口术,进一步损害沟通。医疗
LTS的治疗受到我们对LTS发病机制的认识不足的限制。更好地了解
需要促进LTS的机制来改善这种使人衰弱的疾病的治疗。
先前的研究表明,完整的免疫反应对LTS的发展至关重要。
LTS中免疫应答的表征已经证明了增加的CD 4 + T细胞群体,
巨噬细胞在小鼠LTS模型中的初步研究表明,
减弱LTS纤维化,暗示其病理作用。然而,局部免疫介质和细胞信号传导
在LTS中促进病理性巨噬细胞的途径是未知的。
巨噬细胞活化通过刺激Toll样受体(TLR)来调节。TLRs高度
识别病原体或损伤相关分子模式的保守受体(PAMP/DAMP)和
导致控制表型调节蛋白的下游活化。使用单细胞RNA测序
PI显示LTS巨噬细胞中TLR 4-MyD 88信号通路的表达增加。
此外,我们已经鉴定了LTS组织中DAMP S100 A8/A9的表达增加。S100 A8/A9是一款
已知的TLR 4-MyD 88信号传导激活剂,和我们的鼠LTS模型中的纤维化。这些发现
表明巨噬细胞中TLR 4-MyD 88信号通路可能对LTS发病机制至关重要。然而,在这方面,
S100 A8/A9、TLR 4-MyD 88信号传导和病理性巨噬细胞之间的关系尚未被阐明,
在LTS或其他纤维化疾病中探索,并且可能代表驱动病理性纤维化的关键信号传导轴。
在这项研究中,我们将阐明促进喉气管病理性巨噬细胞的信号网络,
狭窄在目的1中,我们将评估S100 A8/A9对小鼠LTS中巨噬细胞表型和功能的影响。
模型,建立了S100 A8/A9 s促纤维化作用是由巨噬细胞介导的,并确定了关键来源
病理性S100 A8/A9在人LTS和鼠模型中的表达。在目标2中,我们将展示
TLR 4-MyD 88信号在LTS中促进病理性巨噬细胞的作用,并阐明IL 1 β在LTS中促进病理性巨噬细胞的作用。
LTS纤维化。最后,在目标3中,我们将评估S100 A8/A9作为开发
长期插管患者的喉气管狭窄。总的来说,这一应用将导致
深入了解促进巨噬细胞介导的失调的细胞信号网络
炎症和随后的纤维化。确定促进病理性的关键调节途径
LTS中的巨噬细胞将作为减轻纤维化的靶向治疗策略的基础。
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 }}
Kevin Motz其他文献
Kevin Motz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 }}
相似海外基金
A platform for rapidly generating live attenuated enterovirus vaccines
快速生成减毒肠道病毒活疫苗的平台
- 批准号:
24K02286 - 财政年份:2024
- 资助金额:
$ 19.76万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
I-Corps: Translation potential of an efficient method to generate live-attenuated and replication-defective DNA viruses for vaccine development
I-Corps:一种有效方法的转化潜力,可生成用于疫苗开发的减毒活病毒和复制缺陷型 DNA 病毒
- 批准号:
2420924 - 财政年份:2024
- 资助金额:
$ 19.76万 - 项目类别:
Standard Grant
Developing a robust native extracellular matrix to improve islet function with attenuated immunogenicity for transplantation
开发强大的天然细胞外基质,以改善胰岛功能,并减弱移植的免疫原性
- 批准号:
10596047 - 财政年份:2023
- 资助金额:
$ 19.76万 - 项目类别:
Live attenuated non-transmissible (LANT) Klebsiella pneumoniae vaccines
肺炎克雷伯氏菌减毒非传染性 (LANT) 活疫苗
- 批准号:
10742028 - 财政年份:2023
- 资助金额:
$ 19.76万 - 项目类别:
Protecting Pigs From Enzootic Pneumonia: Rational Design Of Safe Attenuated Vaccines.
保护猪免受地方性肺炎:安全减毒疫苗的合理设计。
- 批准号:
BB/X017540/1 - 财政年份:2023
- 资助金额:
$ 19.76万 - 项目类别:
Research Grant
A “Goldilocks” live attenuated poultry vaccine for Infectious Coryza
用于传染性鼻炎的“Goldilocks”家禽减毒活疫苗
- 批准号:
LP210301365 - 财政年份:2023
- 资助金额:
$ 19.76万 - 项目类别:
Linkage Projects
A novel live-attenuated Zika vaccine with a modified 5'UTR
一种带有改良 5UTR 的新型寨卡减毒活疫苗
- 批准号:
10730832 - 财政年份:2023
- 资助金额:
$ 19.76万 - 项目类别:
Combating melanoma with an attenuated bacterial therapeutic
用减毒细菌疗法对抗黑色素瘤
- 批准号:
10659841 - 财政年份:2023
- 资助金额:
$ 19.76万 - 项目类别:
Investigating Host and Viral Factors for Improved Design of Future Live Attenuated Vaccines for IBV
研究宿主和病毒因素以改进未来 IBV 减毒活疫苗的设计
- 批准号:
BB/V016067/1 - 财政年份:2022
- 资助金额:
$ 19.76万 - 项目类别:
Research Grant
L2M NSERC-Bioengineering attenuated Sclerotinia sclerotiorum strains as bioherbicide for cereal production and lawn management
L2M NSERC-生物工程减毒核盘菌菌株作为谷物生产和草坪管理的生物除草剂
- 批准号:
576545-2022 - 财政年份:2022
- 资助金额:
$ 19.76万 - 项目类别:
Idea to Innovation














{{item.name}}会员




