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：
Jeffery D Molkentin
金额：
$ 80.25万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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

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.

抽象的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，心室重塑和纤维化反应一直是最近研究的一个领域，具有重要的医学意义在此，一位发育心脏生物学家提出了双 PI 更新重新提交申请。和成人疾病心脏生物学家研究出生后心脏在成年后如何成熟，然后通过直接旁分泌串扰和 ECM 转换回具有疾病刺激的胎儿样程序反馈在该奖项的过去资助周期中，我们确定了存在的关键监管关系。发育中的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，从而 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。还观察到成纤维细胞表达 GDF10 和表皮生长因子 (EGF) 家族成员多效蛋白 (Ptn) 介导成纤维细胞和肌细胞之间的关键串扰。假设 TGFβ 是一种肌细胞选择性成熟因子，可控制成纤维细胞的活性，从而产生产后心脏内有效的 ECM，也是成人疾病的基础，并且与 Ptn 和 GDF10 平行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双 PI 更新应用有 3 个具体目标：1) 检查如何进行。心肌细胞产生 TGFβ1/2/3 及其随后向心脏成纤维细胞发出的信号是 ECM 新生儿的基础成熟和成人心室重塑，2) 研究心脏成纤维细胞如何产生 ECM 调节因子发育性心肌细胞成熟和成人心脏重塑，部分通过 TGFβ1/2/3 隔离/释放，以及 3) 检查心脏成纤维细胞分泌的生长因子 Ptn 和的功能总的来说，GDF10 在产后心脏发育和成人损伤中的作用将揭示新的内容。出生后心脏成熟的信号机制，并决定这些机制如何运作因此，该计划的影响将是识别新的信号机制。以及可针对人类心脏病进行治疗的效应器，以积极影响心脏重塑和长期纤维化，对治疗先天畸形和发育障碍有额外的影响生长异常。