Cell therapy regulates cardiac healing through innate immune response
细胞疗法通过先天免疫反应调节心脏愈合
基本信息
- 批准号:10561163
- 负责人:
- 金额:$ 3.65万
- 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:2023-02-15 至 2023-04-04
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdoptedAdultApoptosisAreaAtherosclerosisBacteriaBasic ScienceBioinformaticsBiologyBlood VesselsCardiacCardiac DeathCardiac MyocytesCardiovascular systemCause of DeathCell TherapyCell secretionCellsCicatrixClinical DataClinical TrialsCompensationComplement ActivationDNADataDendritic CellsDiseaseEndothelial CellsEventFibroblastsGenesGoalsHeartHeart DiseasesHeart InjuriesHeart failureHumanImmuneImmune responseImmune signalingImmune systemInfarctionInfectionInflammasomeInflammationInflammatoryInflammatory ResponseInfusion proceduresInjection of therapeutic agentInjectionsInjuryInnate Immune ResponseLiteratureLongevityMacrophageMediatingMusMuscle CellsMyocardial InfarctionNatural regenerationNatureNeurosecretory SystemsOutcomePathway interactionsPatientsPattern recognition receptorProcessProductionProteinsRNARejuvenationReportingReproducibilityResearchResolutionRodent ModelSignal PathwaySignal TransductionStimulator of Interferon GenesSting InjuryStructureTherapeuticTherapy trialTimeTissue ExpansionTissuesToll-like receptorsUncertaintyVirusWestern WorldWorkadult stem cellcardiac regenerationcell typedirect applicationfungusgenetic manipulationhealingimprovedin vivoinjuredinnate immune mechanismsischemic injurymouse geneticsneutrophilnovelnovel therapeuticsparacrinephysical propertyprotective effectrepairedresponseresponse to injurystem cell therapystem cellstransdifferentiation
项目摘要
Abstract
Myocardial infarction (MI) due to underlying atherosclerosis is the leading disease
sequela that precipitates heart failure in the Western world. Our ability to treat these
patients and their heart failure has not progressed beyond a mild 20-30% extension in
life span realized some 3 decades ago with neuroendocrine-based management. New
therapeutic avenues are needed, the most dramatic of which would be directly
generating new cardiomyocyte to regenerate the damaged area of heart tissue.
Previous attempts to regenerate the heart through new myocyte production have not
been successful despite more than 15 years of research using adult progenitor cells.
However, studies with cardiac progenitor cells in rodent models did show a functional
benefit to the MI-injured heart, and we and others have identified a novel mechanism of
benefit whereby cell therapy has a rejuvenating effect through refinement of the immune
response. Indeed, we have shown that cell therapy injections can optimize healing,
reduce infarct area expansion and augment scar borderzone physical properties
(Vagnozzi et al., 2020, Nature). These beneficial effects were mediated through
selective macrophage subtype activity in the heart, underscoring the importance of the
immune response in infarct healing and compensation. Here we propose the hypothesis
that selective innate immune response signaling pathways, and macrophage subtype
polarization can be exploited to further heal MI injury and to explain how cell therapy
functions in vivo. Our more specific hypothesis is that MI injury or cell therapy has an
underlying protective component through cGAS-Sting in both cardiomyocytes and
macrophages, and this can be therapeutically exploited to polarize the immune response
for better healing. The specific aims are: AIM #1, To use mouse genetics to identify the
specific immune cell-types in the heart that mediate cell therapy-based cardiac
rejuvenation post-MI injury. AIM #2, To examine the mechanism of innate immune
signaling in the heart through cGAS-Sting. AIM #3, To investigate the mechanisms
whereby cell therapy rejuvenates the post-MI injured heart. Such studies will be critical
for examining how innate immune signaling at the level of macrophages impacts the
heart during an inflammatory injury response or due to cell therapy with the goal of
modifying this response to benefit healing in patients.
摘要
由于动脉粥样硬化引起的心肌梗死(MI)是主要疾病
在西方世界导致心力衰竭的后遗症。我们治疗这些疾病的能力
患者和他们的心力衰竭没有进展超过轻度20-30%的扩展,
大约30年前通过基于神经内分泌的管理实现了寿命。新
需要治疗的途径,其中最引人注目的将是直接
产生新的心肌细胞以再生心脏组织的受损区域。
以前通过产生新的心肌细胞来再生心脏的尝试没有成功。
尽管使用成人祖细胞进行了超过15年的研究,但仍然取得了成功。
然而,在啮齿动物模型中对心脏祖细胞的研究确实显示了功能性的
有益于MI损伤的心脏,我们和其他人已经确定了一种新的机制,
细胞疗法的好处是通过改善免疫系统,
反应事实上,我们已经证明细胞疗法注射可以优化愈合,
减少梗死面积扩大,增加瘢痕边缘区物理性质
(Vageli等人,2020,Nature)。这些有益的影响是通过
选择性巨噬细胞亚型的活动在心脏,强调的重要性,
梗死愈合和补偿中免疫应答。这里我们提出假设
选择性先天免疫反应信号通路和巨噬细胞亚型
极化可以用来进一步治愈心肌梗死损伤,并解释细胞疗法是如何
在体内发挥作用。我们更具体的假设是,心肌梗死损伤或细胞治疗具有
通过cGAS-Sting在心肌细胞和
巨噬细胞,这可以在治疗上用来抑制免疫反应。
为了更好的愈合。具体目标是:目标#1,使用小鼠遗传学来识别
心脏中介导基于细胞疗法的心脏治疗的特定免疫细胞类型
心肌梗死后恢复活力目的#2,研究先天免疫的机制
通过cGAS-Sting在心脏中传递信号。目的#3,研究机制
由此细胞疗法使MI后受损的心脏恢复活力。这些研究将是至关重要的
研究巨噬细胞水平的先天免疫信号如何影响
心脏在炎症损伤反应期间或由于细胞治疗,目的是
改变这种反应以有利于患者的愈合。
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 }}
Jeffery D Molkentin其他文献
Jeffery D Molkentin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('Jeffery D Molkentin', 18)}}的其他基金
Innate Immune Response in Cardiac Healing and Rejuvenation
心脏愈合和恢复活力中的先天免疫反应
- 批准号:
10625955 - 财政年份:2023
- 资助金额:
$ 3.65万 - 项目类别:
Mouse Cardiac Physiology and Surgical Core (Core C)
小鼠心脏生理学和外科核心(核心 C)
- 批准号:
10625950 - 财政年份:2023
- 资助金额:
$ 3.65万 - 项目类别:
Thrombospondin1-regulated atrophy in the heart
血小板反应蛋白1调节的心脏萎缩
- 批准号:
10578361 - 财政年份:2022
- 资助金额:
$ 3.65万 - 项目类别:
Dissecting the role of the cardiac fibroblast in hypertrophy.
剖析心脏成纤维细胞在肥厚中的作用。
- 批准号:
10667595 - 财政年份:2022
- 资助金额:
$ 3.65万 - 项目类别:
Innate immune response signaling in cardiac injury healing
心脏损伤愈合中的先天免疫反应信号
- 批准号:
10350020 - 财政年份:2022
- 资助金额:
$ 3.65万 - 项目类别:
Innate immune response signaling in cardiac injury healing
心脏损伤愈合中的先天免疫反应信号
- 批准号:
10544189 - 财政年份:2022
- 资助金额:
$ 3.65万 - 项目类别:
Dissecting the role of the cardiac fibroblast in hypertrophy.
剖析心脏成纤维细胞在肥厚中的作用。
- 批准号:
10514028 - 财政年份:2022
- 资助金额:
$ 3.65万 - 项目类别:
In vivo role of the fibroblast in muscular dystrophy
成纤维细胞在肌营养不良症中的体内作用
- 批准号:
10377963 - 财政年份:2018
- 资助金额:
$ 3.65万 - 项目类别:
Cardiac fibroblasts in postnatal development and adult injury response
心脏成纤维细胞在产后发育和成人损伤反应中的作用
- 批准号:
10217231 - 财政年份:2018
- 资助金额:
$ 3.65万 - 项目类别:
Cardiac Fibroblasts in Postnatal Development and Adult Injury Response
心脏成纤维细胞在产后发育和成人损伤反应中的作用
- 批准号:
10640493 - 财政年份:2018
- 资助金额:
$ 3.65万 - 项目类别:
相似海外基金
How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
- 批准号:
2315783 - 财政年份:2023
- 资助金额:
$ 3.65万 - 项目类别:
Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
- 批准号:
2719534 - 财政年份:2022
- 资助金额:
$ 3.65万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633211 - 财政年份:2020
- 资助金额:
$ 3.65万 - 项目类别:
Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
- 批准号:
20K01113 - 财政年份:2020
- 资助金额:
$ 3.65万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2436895 - 财政年份:2020
- 资助金额:
$ 3.65万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633207 - 财政年份:2020
- 资助金额:
$ 3.65万 - 项目类别:
Studentship
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
- 批准号:
426559561 - 财政年份:2019
- 资助金额:
$ 3.65万 - 项目类别:
Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
- 批准号:
2236701 - 财政年份:2019
- 资助金额:
$ 3.65万 - 项目类别:
Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
- 批准号:
19K01745 - 财政年份:2019
- 资助金额:
$ 3.65万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
- 批准号:
415543446 - 财政年份:2019
- 资助金额:
$ 3.65万 - 项目类别:
Research Fellowships