Features of PMN Senescence that Lead to Susceptibility to Pneumococcal Infection
导致肺炎球菌感染易感性的中性粒细胞衰老特征
基本信息
- 批准号:10152199
- 负责人:
- 金额:$ 25.53万
- 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:2021-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdoptive TransferAgeAgingBacterial GenesBiological AssayBloodBlood CirculationCRISPR/Cas technologyCell Differentiation processCell LineCell surfaceCharacteristicsChemotactic FactorsChemotaxisClinicalCommunicable DiseasesDataDefectDiseaseDisease ProgressionEicosanoidsElderlyEnvironmentEpigenetic ProcessEpithelialEtiologyFailureFunctional disorderGene ExpressionGenesGenetic TranscriptionHost DefenseImmuneImmunologicsIndividualInfectionInfectious AgentInfiltrationInflammagingInflammationInflammatoryInnate Immune SystemInterleukin-1InterventionLeadLungLung infectionsMatrix MetalloproteinasesMediatingModelingMorphologyMusMyelogenousPhenotypePneumococcal InfectionsPneumococcal PneumoniaPredispositionProcessProductionPulmonary InflammationResistanceRoleSerine ProteaseSerumSourceStreptococcus pneumoniaeSurfaceSystemSystemic diseaseTNF geneTestingTissuesWild Type Mouseage relatedagedcytokinedesignexperiencegenetic approachgenetic manipulationgenome wide screenhigh rewardhigh riskimmune functionimmunosenescenceinsightmacrophagemigrationmutantneutrophilnovel therapeuticsprogenitorsenescencestem cellstranscriptome sequencing
项目摘要
PROJECT ABSTRACT/SUMMARY
Immunosenescence, the age-related decline in immune function, is manifested by an increase in susceptibility
to many infectious diseases, including serious Streptococcus pneumoniae (pneumococcus) infection. Acute
pulmonary inflammation is characteristic of pneumococcal lung infection and may exacerbate tissue damage
and disease progression. The elderly suffer from `Inflammaging', the age-dependent increase in basal and
induced levels of proinflammatory cytokines. Further, polymorphonuclear leukocytes (PMNs) from elderly
individuals display defects in several activities, such as chemotaxis, opsonophagocytic killing, and ROS
production. Using a model of intratracheal challenge of wild-type mice, which recapitulates the susceptibility to
pneumococcal infection among the elderly, our preliminary data suggests that PMN dysfunction may be a
primary cause of the increased susceptibility to pneumococcal pneumonia. Furthermore, adoptive transfer of
PMNs from young mice into aged mice conferred resistance to pneumococcal lung challenge, indicating that
young PMNs possess defense functions that are lacking in aged PMNs. Comparing the gene expression of
uninfected or pneumococcus-exposed PMNs from young and aged mice (by our collaborator Dr. Bou Ghanem)
revealed age-dependent expression differences. However, the precise PMN dysfunction leading to age-
dependent susceptibility remains unknown and is a focus of this proposal. Here we propose to identify the
specific PMN functions that diminish with age and result in the susceptibility to pneumococcal lung infection, as
well as systematically test the degree to which age-associated, PMN-mediated susceptibility is due to a
diminished defense and/or an enhanced disease-promoting activity. By pinpointing the key host defenses that
degrade with age and result in invasive pneumococcal disease, these studies will not only facilitate precisely
targeted interventions against a major infectious agent, but also provide insight into the aging innate immune
system that may lead to novel therapies against other infections that disproportionately afflict the elderly. In
addition, taking a high-risk, high-reward approach, we seek to treat PMNs derived from HoxB8 progenitor cell
lines with low levels of inflammatory cytokines found in the bloodstream of the aged host to confer on these
PMNs an aged phenotypic profile with respect to PMN activities and RNA expression. Our Aims are (1)
Characterize PMN functions that diminish upon aging and recapitulation these defects in PMNs derived from
immortalized myeloid progenitors. (2) Assess the degree to which aged PMNs not only fail to defend against
infection but also actively promote pneumococcal disease, thus contributing to age-associated susceptibility to
S. pneumoniae.
项目摘要/总结
免疫衰老,即与年龄相关的免疫功能下降,表现为易感性增加
许多传染病,包括严重的肺炎链球菌(肺炎球菌)感染。急性
肺部炎症是肺炎球菌肺部感染的特征,可能会加剧组织损伤
和疾病进展。老年人患有“炎症”,即基础和炎症水平随年龄增长而增加
诱导促炎细胞因子水平。此外,来自老年人的多形核白细胞(PMN)
个体在多种活动中表现出缺陷,例如趋化性、调理吞噬杀伤和活性氧
生产。使用野生型小鼠的气管内攻击模型,该模型概括了对
对于老年人肺炎球菌感染,我们的初步数据表明PMN功能障碍可能是一个
肺炎球菌肺炎易感性增加的主要原因。此外,收养转移
从年轻小鼠到老年小鼠的 PMN 赋予了对肺炎球菌肺部攻击的抵抗力,这表明
年轻的 PMN 具有老年 PMN 所缺乏的防御功能。比较基因表达
来自年轻和老年小鼠的未感染或肺炎球菌暴露的 PMN(由我们的合作者 Bou Ghanem 博士提供)
揭示了年龄依赖性的表达差异。然而,精确的 PMN 功能障碍导致年龄
依赖性易感性仍然未知,也是本提案的重点。在这里我们建议确定
特定的 PMN 功能会随着年龄的增长而减弱,并导致对肺炎球菌肺部感染的易感性,如
以及系统地测试与年龄相关的、PMN 介导的易感性在多大程度上是由于
防御能力减弱和/或疾病促进活动增强。通过查明关键的宿主防御
随着年龄的增长而降解并导致侵袭性肺炎球菌疾病,这些研究不仅将促进精确
针对主要传染源的有针对性的干预措施,同时也提供了对老化先天免疫的深入了解
该系统可能会带来针对老年人不成比例的其他感染的新疗法。在
此外,我们采取高风险、高回报的方法,寻求治疗源自 HoxB8 祖细胞的中性粒细胞
在老年宿主的血液中发现具有低水平炎症细胞因子的细胞系,以赋予这些
PMN 是有关 PMN 活性和 RNA 表达的老化表型特征。我们的目标是 (1)
描述 PMN 功能随着年龄的增长而减弱,并概括这些 PMN 中的缺陷源自
永生化骨髓祖细胞。 (2) 评估老化的 PMN 不仅无法防御的程度
感染,还会积极促进肺炎球菌疾病,从而导致与年龄相关的易感性
肺炎链球菌。
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 }}
JOHN M LEONG其他文献
JOHN M LEONG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('JOHN M LEONG', 18)}}的其他基金
Features of PMN Senescence that Lead to Susceptibility to Pneumococcal Infection
导致肺炎球菌感染易感性的中性粒细胞衰老特征
- 批准号:
10356895 - 财政年份:2021
- 资助金额:
$ 25.53万 - 项目类别:
Effect of Shiga toxin, OMVs, and innate immune cells on epithelial integrity of human colonoids during EHEC infection
志贺毒素、OMV 和先天免疫细胞对肠出血性大肠杆菌感染期间人结肠上皮完整性的影响
- 批准号:
10112822 - 财政年份:2020
- 资助金额:
$ 25.53万 - 项目类别:
Effect of Shiga toxin, OMVs, and innate immune cells on epithelial integrity of human colonoids during EHEC infection
志贺毒素、OMV 和先天免疫细胞对肠出血性大肠杆菌感染期间人结肠上皮完整性的影响
- 批准号:
9978339 - 财政年份:2020
- 资助金额:
$ 25.53万 - 项目类别:
FASEB SRC on Molecular Pathogenesis: Mechanisms of Infectious Disease
FASEB SRC 关于分子发病机制:传染病机制
- 批准号:
8908265 - 财政年份:2015
- 资助金额:
$ 25.53万 - 项目类别:
CRASP-mediated Serum Resistance by Borrelia burgdorferi
CRASP 介导的伯氏疏螺旋体的血清耐药性
- 批准号:
8953318 - 财政年份:2015
- 资助金额:
$ 25.53万 - 项目类别:
CRASP-mediated Serum Resistance by Borrelia burgdorferi
CRASP 介导的伯氏疏螺旋体的血清耐药性
- 批准号:
9087098 - 财政年份:2015
- 资助金额:
$ 25.53万 - 项目类别:
Stx-mediated disease and immunomodulatory effectors of enterohemorrhagic E.coli
Stx介导的肠出血性大肠杆菌疾病和免疫调节效应器
- 批准号:
8570980 - 财政年份:2013
- 资助金额:
$ 25.53万 - 项目类别:
Stx-mediated disease and immunomodulatory effectors of enterohemorrhagic E.coli
Stx介导的肠出血性大肠杆菌疾病和免疫调节效应器
- 批准号:
8692645 - 财政年份:2013
- 资助金额:
$ 25.53万 - 项目类别:
EHEC-induced actin rearrangement and Stx2 translocation across epithelium
EHEC 诱导的肌动蛋白重排和 Stx2 跨上皮易位
- 批准号:
8207883 - 财政年份:2011
- 资助金额:
$ 25.53万 - 项目类别:
EHEC-induced actin rearrangement and Stx2 translocation across epithelium
EHEC 诱导的肌动蛋白重排和 Stx2 跨上皮易位
- 批准号:
8029721 - 财政年份:2011
- 资助金额:
$ 25.53万 - 项目类别:
相似海外基金
Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
- 批准号:
10682121 - 财政年份:2023
- 资助金额:
$ 25.53万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10576370 - 财政年份:2022
- 资助金额:
$ 25.53万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10387023 - 财政年份:2022
- 资助金额:
$ 25.53万 - 项目类别:
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10248409 - 财政年份:2019
- 资助金额:
$ 25.53万 - 项目类别:
A phase I clinical study of adoptive transfer of regulatory T cells (Tregs) and low-dose interleukin-2 (IL-2) for the treatment of chronic graft-versus-host disease (GVHD): gene-marking to inform rational combination therapy
调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
- 批准号:
nhmrc : GNT1163111 - 财政年份:2019
- 资助金额:
$ 25.53万 - 项目类别:
Project Grants
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10462684 - 财政年份:2019
- 资助金额:
$ 25.53万 - 项目类别:
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
基因编辑的淋巴祖细胞用于过继转移作为原发性免疫缺陷的治疗
- 批准号:
398018062 - 财政年份:2018
- 资助金额:
$ 25.53万 - 项目类别:
Research Grants
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9308643 - 财政年份:2017
- 资助金额:
$ 25.53万 - 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9447149 - 财政年份:2017
- 资助金额:
$ 25.53万 - 项目类别:
Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes
通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA
- 批准号:
8893915 - 财政年份:2014
- 资助金额:
$ 25.53万 - 项目类别:














{{item.name}}会员




