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
基本信息
- 批准号:10640493
- 负责人:
- 金额:$ 80.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAreaAwardBackBirthCardiacCardiac MyocytesCollagenCongenital AbnormalityDevelopmentDiseaseDisease ProgressionEpidermal Growth FactorExtracellular MatrixFamily memberFeedbackFibroblastsFibrosisFundingFutureGDF10 geneGoalsGrowthGrowth FactorHeartHeart DiseasesHeart failureHumanHypertrophyInjuryInvestigationMediatingMedicalMuscle CellsMyofibroblastNeonatalOrganPathway interactionsPatientsProductionProliferatingSignal TransductionTherapeuticTransforming Growth Factor betaVentricular Remodelingcardiogenesiscell typecoronary fibrosisfetalgrowth differentiation factor 10heart functionmetaplastic cell transformationnovelnovel therapeuticsparacrinepleiotrophinpostnatalpostnatal developmentprogramsresponseresponse to injurytherapeutic target
项目摘要
Abstract
The cardiac fibroblast and its ability to convert into a myofibroblast for extracellular matrix (ECM) production,
ventricular remodeling and the fibrotic response has been an area of recent investigation with important medical
relevance. Here, a dual-PI renewal resubmission application is proposed by a developmental cardiac biologist
and adult disease-based cardiac biologist to address how the postnatal heart matures in adulthood and then
transitions back to a fetal-like program with disease stimulation through direct paracrine crosstalk and ECM
feedback. During the past funding cycle of this award, we identified key regulatory relationships that exist
between myocytes and fibroblasts in both the developing and diseased adult heart, whereby the ECM and
transforming growth factor-β (TGFβ) served as an integrating platform between these 2 cell-types. We have
also observed that fibroblast-expressed GDF10 and the epidermal growth factor (EGF) family member
pleiotrophin (Ptn) mediate critical crosstalk between fibroblasts and myocytes. Here, we will investigate the
hypothesis that TGFβ is a myocyte selective maturation factor that controls fibroblast activity in generating an
effective ECM within the postnatal heart that also underlies adult disease, and that parallel Ptn and GDF10
signaling crosstalk further regulates fibroblast proliferation and promotes cardiomyocyte hypertrophy in
development and disease. The dual-PI renewal application has 3 specific aims: 1) To examine how
cardiomyocyte generated TGFβ1/2/3 and its subsequent signaling to cardiac fibroblasts underlie ECM neonatal
maturation and adult ventricular remodeling, 2) To examine how cardiac fibroblast generated ECM regulates
developmental cardiomyocyte maturation and adult heart remodeling, in part through TGFβ1/2/3
sequestration/release, and 3) To examine the function of the cardiac fibroblast-secreted growth factors Ptn and
GDF10 in postnatal heart development and adult injury. Collectively, these specific aims will uncover novel
signaling mechanisms that underlie heart maturation just after birth and determine how these mechanisms are
redeployed in disease. Thus, the impact of this program will be the identification of novel signaling mechanisms
and effectors that can be therapeutically targeted in human heart disease to positively effect cardiac remodeling
and longstanding fibrosis, with added implications for treating congenital malformations and developmental
growth abnormalities.
摘要
心脏成纤维细胞及其转化为肌成纤维细胞以产生细胞外基质(ECM)的能力,
心室重构和纤维化反应是近年来重要医学研究的领域,
本案无关在这里,双PI更新重新提交申请是由发育心脏生物学家提出的
和成人疾病为基础的心脏生物学家,以解决如何出生后的心脏在成年期成熟,
通过直接旁分泌串扰和细胞外基质,通过疾病刺激过渡回胎儿样程序
反馈在该奖项的上一个融资周期中,我们确定了存在的关键监管关系
发育中和患病的成年心脏中的肌细胞和成纤维细胞之间存在着相互作用,其中ECM和
转化生长因子-β(TGFβ)充当这两种细胞类型之间的整合平台。我们有
还观察到成纤维细胞表达的GDF 10和表皮生长因子(EGF)家族成员,
多效生长因子(Ptn)介导成纤维细胞和肌细胞之间关键串扰。在这里,我们将调查
假设TGFβ是一种肌细胞选择性成熟因子,控制成纤维细胞活性,
出生后心脏内的有效ECM也是成人疾病的基础,并且平行的Ptn和GDF 10
信号串扰进一步调节成纤维细胞增殖,并促进心肌细胞肥大,
发展和疾病。双PI续期申请有3个具体目标:1)研究如何
心肌细胞产生TGFβ1/2/3及其随后向心脏成纤维细胞的信号传导是新生儿ECM的基础
成熟和成人心室重塑,2)检查心脏成纤维细胞产生的ECM如何调节
发育心肌细胞成熟和成人心脏重塑,部分通过TGFβ1/2/3
螯合/释放,和3)检查心脏成纤维细胞分泌的生长因子Ptn和Ptn的功能。
GDF 10在出生后心脏发育和成人损伤中的作用总的来说,这些具体的目标将揭示新的
这些信号机制是出生后心脏成熟的基础,并决定了这些机制是如何
重新部署在疾病。因此,该计划的影响将是识别新的信号传导机制
以及可以在人类心脏病中治疗靶向以积极影响心脏重塑的效应物
和长期的纤维化,以及对治疗先天性畸形和发育的额外影响,
生长异常
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:
$ 80.25万 - 项目类别:
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
- 批准号:
10561163 - 财政年份:2023
- 资助金额:
$ 80.25万 - 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:
$ 80.25万 - 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:
$ 80.25万 - 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:
$ 80.25万 - 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:
$ 80.25万 - 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:
$ 80.25万 - 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:
$ 80.25万 - 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:
$ 80.25万 - 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:
$ 80.25万 - 项目类别:
相似海外基金
History of Community and Adult Education in Old Coal Mining Area in Northern Kyushu
九州北部老煤矿区社区与成人教育的历史
- 批准号:
26780447 - 财政年份:2014
- 资助金额:
$ 80.25万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
High Risk Adult Hepatitis B Vaccination Pilot -Program Area 7
高危成人乙型肝炎疫苗接种试点 - 计划领域 7
- 批准号:
8506903 - 财政年份:2012
- 资助金额:
$ 80.25万 - 项目类别:
The San Francisco Bay Area Adult Glioma Survival Study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
7253800 - 财政年份:2007
- 资助金额:
$ 80.25万 - 项目类别:
San Francisco Bay area adult glioma survival study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
6686704 - 财政年份:2002
- 资助金额:
$ 80.25万 - 项目类别:
The San Francisco Bay Area Adult Glioma Survival Study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
8258656 - 财政年份:
- 资助金额:
$ 80.25万 - 项目类别:
San Francisco Bay area adult glioma survival study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
7550487 - 财政年份:
- 资助金额:
$ 80.25万 - 项目类别:
The San Francisco Bay Area Adult Glioma Survival Study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
8099448 - 财政年份:
- 资助金额:
$ 80.25万 - 项目类别:
San Francisco Bay area adult glioma survival study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
7550482 - 财政年份:
- 资助金额:
$ 80.25万 - 项目类别:
The San Francisco Bay Area Adult Glioma Survival Study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
7885642 - 财政年份:
- 资助金额:
$ 80.25万 - 项目类别:
San Francisco Bay area adult glioma survival study
旧金山湾区成人神经胶质瘤生存研究
- 批准号:
7550492 - 财政年份:
- 资助金额:
$ 80.25万 - 项目类别: