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Exploring heterogeneity of cardiac fibroblasts to reverse fibrosis

探索心脏成纤维细胞的异质性以逆转纤维化

基本信息

批准号：
8751716
负责人：
Reza Ardehali
金额：
$ 231万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cardiac fibroblasts (CFs), the most abundant nonmyocyte cell type in the heart, provide continuity between cardiomyocytes, maintain the structural integrity of the myocardium and coronary vasculature and are the predominant cellular mediators of fibrosis in the heart in response to injury. Recent efforts to induce lineage conversion of CFs to cardiomyocytes and endothelial cells, in an effort to generate new contractile tissue and blood vessels, have been limited by an inefficient reprogramming. A robust and efficient method involves precise stoichiometry as well as certain levels of expression of reprogramming factors in a temporally defined sequence. Additionally, a fundamental obstacle remains the inability to identify a homogenous population of fibroblasts susceptible to reprogramming. The central hypothesis of this proposal is that a discrete population of CFs that share the same embryonic origin as cardiomyocytes or endothelial cells may have an epigenetic 'memory' that predisposes them to direct reprogramming following a dose-titratable, temporally-controlled, and stage-specific sequential delivery of required transcription factors (TFs). By using modified RNA (modRNA) as a non-integrating genetic delivery system, we can achieve a controlled 'pulse-like' expression of core TFs and avoid potential issues associated with viral integration. To address our hypotheses, we will use lineage-tracing experiments to identify discrete populations of CFs that share a common ancestor with cardiomyocytes and/or with endothelial cells. Synthetic modRNAs that encode core-reprogramming TFs will be used for lineage conversion both in vitro and in vivo. We believe that the native milieu of the intact heart, surrounding contractile cells, growth factors ad cytokines will provide a more permissive environment for functional reprogramming. Therefore, it is expected that delivery of modRNA to the injured area of the heart where there is active and dynamic proliferation of fibroblasts could result in an efficient reprogramming of CFs to cardiomyocytes and endothelial cells. The challenges associated with this project are substantial; however, its potential scientific and clinical impact is significant. We are confident that our meticulous experimental design and innovative approach will unravel the origin of CFs and their contribution to cardiac development and injury. Additionally, our findings will open entirely new avenues to manipulate CFs in vivo using modRNAs to restore damaged myocardium and reverse fibrosis.

描述（由申请人提供）：心脏成纤维细胞（CF）是心脏中最丰富的非肌细胞细胞类型，提供心肌细胞之间的连续性，维持心肌和冠状血管的结构完整性，是心脏对损伤做出反应时纤维化的主要细胞介质。最近的努力，以诱导CF的谱系转换为心肌细胞和内皮细胞，在努力产生新的收缩组织和血管，已受到限制的效率低下的重编程。一种稳健且有效的方法涉及精确的化学计量以及在时间上限定的序列中重编程因子的一定水平的表达。此外，一个根本的障碍仍然是无法识别一个同质群体的成纤维细胞容易重编程。该建议的中心假设是，与心肌细胞或内皮细胞共享相同胚胎起源的离散CFs群体可能具有表观遗传“记忆”，该表观遗传“记忆”使其倾向于在剂量可滴定、时间控制和阶段特异性顺序递送所需转录因子（TF）后直接重编程。通过使用修饰的RNA（modRNA）作为非整合的遗传递送系统，我们可以实现核心TF的受控的“脉冲样”表达，并避免与病毒整合相关的潜在问题。为了解决我们的假设，我们将使用谱系追踪实验来识别与心肌细胞和/或与内皮细胞共享共同祖先的CFs的离散群体。编码核心重编程TF的合成modRNA将用于体外和体内的谱系转换。我们相信完整心脏的自然环境，周围的收缩细胞，生长因子和细胞因子将为功能重编程提供一个更宽松的环境。因此，预期将modRNA递送至存在成纤维细胞的活跃和动态增殖的心脏损伤区域可导致CF向心肌细胞和内皮细胞的有效重编程。与该项目相关的挑战是巨大的;然而，其潜在的科学和临床影响是显著的。我们相信我们细致的实验设计和创新的方法将揭开CF的起源及其对心脏发育和损伤的贡献。此外，我们的研究结果将开辟全新的途径，使用modRNA在体内操纵CF，以恢复受损的心肌和逆转纤维化。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Arrhythmia in stem cell transplantation.

DOI：
10.1016/j.ccep.2015.03.012
发表时间：
2015-06
期刊：
Cardiac electrophysiology clinics
影响因子：
0
作者：
Almeida SO;Skelton RJ;Adigopula S;Ardehali R
通讯作者：
Ardehali R

Harnessing the versatility of PLGA nanoparticles for targeted Cre-mediated recombination.

利用 PLGA 纳米粒子的多功能性进行 Cre 介导的靶向重组。

DOI：
10.1016/j.nano.2019.02.027
发表时间：
2019
期刊：
Nanomedicine : nanotechnology, biology, and medicine
影响因子：
0
作者：
Nguyen,NgocB;Chen,Cheng-Han;Zhang,Yulong;Zhao,Peng;Wu,BenjaminM;Ardehali,Reza
通讯作者：
Ardehali,Reza

Direct cardiac reprogramming: A new frontier in heart regeneration.

直接心脏重编程：心脏再生的新领域。