Unraveling the role of endothelium in chemotherapy-induced cardiotoxicity

揭示内皮在化疗引起的心脏毒性中的作用

基本信息

批准号：
10543095
负责人：
Nazish Sayed
金额：
$ 39.35万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543095
关键词：
3-Dimensional Acute Address Affect Aftercare Animal Model Anthracycline Antineoplastic Agents Atherosclerosis Attention Biochemical Biomedical Engineering CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular Physiology Cardiovascular system Cells Chromatin Chromosome Mapping Chronic Coculture Techniques Collaborations Communication Complex Computational Biology Data Development Dose Doxorubicin Endothelial Cells Endothelium Environment Exhibits Exposure to Functional disorder Gene Deletion Gene Expression Generations Genomic DNA Goals Health Heart Heart failure Human Impairment Kinetics Knowledge Left Ventricular Ejection Fraction Ligands Malignant Neoplasms Mediating Membrane Mitochondria Modeling Molecular Morbidity - disease rate Mus Muscle Cells Myocardial dysfunction Oncology Organ Paracrine Communication Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Phenotype Physiology Play Positioning Attribute Reactive Oxygen Species Research Personnel Role Signal Transduction Site Therapeutic Topoisomerase II inhibition Trastuzumab Type I DNA Topoisomerases Vascular Diseases Wing Work cardiac tissue engineering cell injury cell type chemotherapy endothelial stem cell gene regulatory network genome editing heart cell improved in vivo induced pluripotent stem cell induced pluripotent stem cell technology insight interdisciplinary approach mechanical properties mortality mouse model multidisciplinary myocardial injury next generation sequencing novel paracrine pharmacologic promoter receptor response side effect single cell technology single-cell RNA sequencing stem cell biology tool transcription factor

项目摘要

Project Summary/Abstract Doxorubicin is a highly effective chemotherapy drug commonly used to treat multiple cancers, but its use is limited due to cardiotoxicity. Cardiotoxicity can range from asymptomatic reduction in left ventricular ejection fraction to highly symptomatic heart failure (Class III to IV). Acute doxorubicin-induced cardiotoxicity (DIC) occurs in ~11% of patients, and long-term cardiotoxic side effects can develop in ~36% of patients up to 10 years after treatment. Despite being the most effective class of anti-cancer drug and widely used since last five decades, the molecular mechanisms that underly DIC remain poorly understood. To date, three major inter- related mechanisms for cardiotoxic effects of doxorubicin have been proposed: (i) generation of reactive oxygen species (ROS) and subsequent membrane damage, (ii) inhibition of topoisomerase II-β (TOP2B) topoisomerase I mitochondrial (TOP1MT), and (iii) modulation of intracellular calcium release. However, as cardiotoxicity in DIC patients may not emerge for years or decades, a better understanding of the different mechanisms in DIC across different cardiac cell types and their crosstalk can have significant implications on the search for therapeutics. The endothelium is a critical component of the cardiovascular system that forms a protective barrier for CMs and releases paracrine factors to maintain CM health and function. It has been shown that DOX disrupts the normal endothelial physiology by damaging ECs that can lead to the development of severe chronic vascular diseases such as atherosclerosis, which often leads to cardiac dysfunction. With the knowledge that dysfunctional ECs can have a negative impact on CM function, we need a better understanding of the integral role of ECs in the development of doxorubicin-induced myocardial injury. Despite impressive progress, little attention has been given to the potential importance of cell-to-cell signaling between ECs and CMs, despite the fact that ECs serve a paracrine function to enhance signaling in CMs, especially in context to pharmacological stimulation. This knowledge gap impedes our comprehensive understanding of organ dysfunction at a multi- cellular level. The overarching goal of our proposal is to use a multidisciplinary approach that integrates human iPSCs, bioengineering tools, and NGS to gain novel insights into the pathogenesis of DIC. We will pursue three specific aims. In Aim 1: we will establish an experimental platform to study the role of ECs in DIC. For this, we will recapitulate the EC-CM crosstalk in DIC patient’s iPSC-derived cells with 3D engineered heart tissues (EHTs). In Aim 2: we will decipher the mechanism of EC-CM crosstalk in EHTs treated with DOX using single- cell approaches (scRNA-seq and scATAC-seq). In Aim 3: we will validate the key regulatory players of EC-CM crosstalk in an animal model of DIC. Our proposal is supported by compelling preliminary data from a multi- disciplinary team of investigators. We believe we are well positioned to achieve the project goals within five years.

项目概要/摘要阿霉素是一种高效的化疗药物，常用于治疗多种癌症，但其用途由于心脏毒性而受到限制。心脏毒性的范围包括无症状的左心室射血减少。严重症状性心力衰竭（III 至 IV 级）。约 11% 的患者会发生这种情况，约 36% 的患者可能会出现长期心脏毒性副作用（最多 10 年）尽管是最有效的一类抗癌药物，并且自过去五年以来被广泛使用。几十年来，DIC 的分子机制至今仍知之甚少，其中三个主要的相互作用。已提出阿霉素心脏毒性作用的相关机制：(i) 产生反应性氧簇 (ROS) 和随后的膜损伤，(ii) 拓扑异构酶 II-β (TOP2B) 的抑制拓扑异构酶 I 线粒体 (TOP1MT)，以及 (iii) 细胞内钙释放的调节。 DIC 患者的心脏毒性可能数年或数十年才会出现，因此需要更好地了解不同的不同心脏细胞类型之间的 DIC 机制及其串扰可能对寻找治疗方法。内皮细胞是心血管系统的重要组成部分，为 CM 形成保护屏障并释放旁分泌因子以维持 CM 健康和功能。已经证明 DOX 会破坏细胞的正常功能。通过破坏内皮细胞来破坏正常的内皮生理机能，从而导致严重的慢性血管疾病的发生动脉粥样硬化等疾病通常会导致心脏功能障碍。功能失调的 EC 会对 CM 功能产生负面影响，我们需要更好地了解积分 ECs 在阿霉素诱导的心肌损伤发展中的作用尽管取得了令人瞩目的进展，但进展甚微。尽管 EC 和 CM 之间的细胞间信号传导的潜在重要性已受到关注事实上，EC 具有旁分泌功能，可以增强 CM 中的信号传导，特别是在药理学方面这种知识差距阻碍了我们对多器官功能障碍的全面理解。我们提案的总体目标是使用整合人类的多学科方法。我们将利用 iPSC、生物工程工具和 NGS 来深入了解 DIC 的发病机制。具体目标：我们将建立一个实验平台来研究EC在DIC中的作用。将重现 DIC 患者 iPSC 衍生细胞与 3D 工程心脏组织中的 EC-CM 串扰 (EHT) 在目标 2 中：我们将使用单-破译 DOX 处理的 EHT 中 EC-CM 串扰的机制。细胞方法（scRNA-seq 和 scATAC-seq）在目标 3 中：我们将验证 EC-CM 的关键监管参与者。 DIC 动物模型中的串扰得到了多个令人信服的初步数据的支持。我们相信我们有能力在五年内实现项目目标。年。