TREK-1 in fibroblast differentiation and cardiac fibrosis development

TREK-1 在成纤维细胞分化和心脏纤维化发展中的作用

基本信息

批准号：
9113434
负责人：
Dennis Abraham
金额：
$ 15.46万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-22 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113434
关键词：
Academic Medical Centers Accounting Address Affect Animal Model Attenuated Award Biomechanics Cadherins Cardiac Cicatrix Clinical Collagen Congestive Heart Failure Coupled Couples Cre-LoxP Data Development Diagnosis Diastole Diastolic heart failure EFRAC Environment Event Exhibits Fibroblasts Fibrosis Foundations Functional disorder Future Generations Goals Growth Factor Receptors Health Heart Diseases Heart Hypertrophy Heart failure Human Hypertrophy In Vitro Injury Knock-out Knockout Mice Mentors Mentorship Methods Mission Modeling Molecular Molecular Biology Molecular Biology Techniques Mus Muscle Cells Myocardial Infarction Myofibroblast Patient Education Personnel Management Phenotype Potassium Channel Production Public Health Research Research Personnel Research Training Signal Transduction Spectrin Stretching Technology Testing Transforming Growth Factor beta Receptors Transforming Growth Factors Ventricular Wild Type Mouse Work base career development coronary fibrosis cytokine effective therapy experience in vivo insight interstitial mouse model mutant new therapeutic target novel novel strategies overexpression potassium channel protein TREK-1 pressure research study response skills targeted treatment transdifferentiation treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Heart failure with preserved ejection (HFpEF) is rapidly coming the most common form of congestive heart failure, and there are currently limited effective therapies. The lack of effective therapies underscores the urgent need to identify novel therapeutic targets to treat HFpEF. A potential treatment target is abnormal ventricular filling during diastole or diastolic dysfunction due to cardiac fibrosis. While anti-fibrosis therapies hav a powerful effect on diastolic dysfunction, such therapies in humans have yielded disappointing results. Our proposal offers a novel approach to this problem by focusing on the activation of pro-fibrotic signaling downstream of transforming growth factor receptor beta (TGF�by the stretch sensitive potassium channel TREK-1. Mice lacking TREK-1 develop exaggerated cardiac hypertrophy in response to pressure overload yet still maintain normal diastolic function. Our preliminary data suggest that this phenotype is explained by altered fibroblast activity and disruption of TGF�ignaling. The overall objective of this proposal is to investigate how TREK-1 regulates cardiac fibrosis in response to pressure overload and to allow me to develop the skills to become an independent investigator. Our central hypothesis is that the loss of TREK-1 function attenuates cardiac fibrosis through disrupted TGF�ignaling and diminished fibroblast activation. We will address this hypothesis, using the following approach: 1) we will determine how TREK-1 affects fibroblast function and differentiation using cardiac fibroblasts isolated from TREK-1 knockout mice and by utilizing a myocardial infarction model, 2) we will determine how TREK-1 affects TGF�ediated signaling by biomechanical stretch using an in vitro cellular stretch model and 3) we will investigate how the loss of TREK-1 in fibroblasts affects response to cardiac injury using a conditional TREK-1 knockout mouse. The proposed experiments will generate insights into the development of diastolic dysfunction due to cardiac fibrosis and novel targets to treat HFpEF. Over next several years, I hope the following skills: 1) generation and utilization of animal models of cardiac disease, 2) molecular biology techniques, 3) methods to study cardiac mechanotransduction and 4) personnel management. These skills coupled with the data obtained during the award period will allow me to achieve my long-term goal of becoming an independent investigator focused on identifying molecular mechanisms underlying HFpEF. My mentor for this award proposal is Dr. Howard Rockman, who is a leader in the field of molecular biology and has extensive experience as a research mentor. Moreover, my mentorship team, my clinical experience in treating heart failure patients and the training environment at Duke University Medical Center is optimal for achieving both the career development and scientific objectives outlined this proposal.

描述（由申请人提供）：射血保留性心力衰竭（HFpEF）正在迅速成为充血性心力衰竭的最常见形式，目前有效的治疗方法有限，缺乏有效的治疗方法强调了迫切需要确定新的治疗靶点。治疗 HFpEF 的一个潜在治疗目标是心脏纤维化导致的舒张期心室充盈异常或舒张功能障碍，而抗纤维化治疗对舒张功能障碍具有强大的作用，但此类疗法在人类中。我们的建议提供了一种解决这个问题的新方法，重点关注通过拉伸敏感钾通道 TREK-1 激活转化生长因子受体 β（TGF-）下游的促纤维化信号。缺乏 TREK-1 的小鼠会发育。我们的初步数据表明，这种表型是由成纤维细胞活性改变和 TGF 信号传导破坏来解释的。 TREK-1 调节心脏纤维化以应对压力超负荷，并使我能够培养成为独立研究者的技能。我们的中心假设是，TREK-1 功能的丧失会通过破坏 TGF 信号传导和减少成纤维细胞活化来减轻心脏纤维化。我们将使用以下方法解决这一假设：1) 我们将使用从 TREK-1 敲除中分离出的心脏成纤维细胞来确定 TREK-1 如何影响成纤维细胞功能和分化小鼠并利用心肌梗死模型，2) 我们将使用体外细胞拉伸模型确定 TREK-1 如何通过生物力学拉伸影响 TGF 介导的信号传导，3) 我们将研究成纤维细胞中 TREK-1 的丢失如何影响反应使用条件 TREK-1 敲除小鼠来研究心脏损伤。拟议的实验将深入了解心脏纤维化引起的舒张功能障碍以及治疗 HFpEF 的新靶点。未来几年，我希望掌握以下技能：1）心脏病动物模型的生成和利用，2）分子生物学技术，3）研究心脏机械传导的方法以及4）人员管理这些技能与过程中获得的数据相结合。奖励期将使我能够实现成为一名独立研究者的长期目标，专注于确定 HFpEF 的分子机制。我的本次奖励提案的导师是 Howard Rockman 博士，他是分子生物学领域的领导者，拥有广泛的研究成果。作为研究导师的经验。此外，我的导师团队、我治疗心力衰竭患者的临床经验以及杜克大学医学中心的培训环境对于实现该提案概述的职业发展和科学目标来说是最佳的。