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

• 批准号: 10340657
• 负责人: Nazish Sayed
• 金额: $ 39.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10340657
• 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; Cardiotoxicity; Cardiovascular Physiology; Cardiovascular system; Cells; Chromatin; Chronic; Coculture Techniques; Collaborations; Communication; Complex; Computational Biology; Data; Development; Dose; Doxorubicin; Endothelial Cells; Endothelium; Environment; Exhibits; Exposure to; Functional disorder; Gene Expression; Generations; Genes; Genomic DNA; Goals; Health; Heart; Heart failure; Human; Impairment; Kinetics; Knowledge; Lead; 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; Pharmacology; Phenotype; Physiology; Play; Positioning Attribute; Reactive Oxygen Species; Research Personnel; Role; Signal Transduction; Site; Therapeutic; Topoisomerase II; Trastuzumab; Type I DNA Topoisomerases; Vascular Diseases; Wing; Work; base; 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; predictive modeling; promoter; receptor; response; side effect; single cell technology; single-cell RNA sequencing; stem cell biology; tool; transcription factor

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.

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