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Determinants of Arrhythmogenic Risk In Arrhythmogenic Cardiomyopathies and Mitral Valve Prolapse

致心律失常性心肌病和二尖瓣脱垂的致心律失常风险的决定因素

基本信息

批准号：
10853894
负责人：
Farah Sheikh
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10853894
关键词：
Administrative Supplement Affect Age Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Biomedical Engineering Bone Marrow Cardiac Myocytes Cardiology Cardiovascular system Cell Nucleus Cells Cicatrix Collaborations Communication Data Desmosomes Disease EKG QRS Complex Electric Countershock Electrophysiology (science)Etiology Exhibits Faculty Fibrosis Fluorescent in Situ Hybridization Functional disorder Funding Future General Population Genes Goals Heart Heart Abnormalities Heterogeneity Histologic Human Injury Knock-in Mouse Location Magnetic Resonance Imaging Malignant - descriptor Manuscripts Measurement Mechanics Medial Methods Mitral Valve Prolapse Modeling Molecular Molecular Target Mus Mutant Strains Mice Mutation Myeloid Cells Myocardial Infarction Myocardium Nature Neighborhoods Pathogenesis Pathologic Pathway interactions Publishing RNA RNA Splicing Research Resolution Risk Risk Assessment Stereotyping Study models Sudden Death Surface Techniques Technology Assessment Telemetry Therapeutic Ventricular Ventricular Arrhythmia Ventricular Premature Complexes Ventricular Tachycardia arrhythmogenic cardiomyopathy hemodynamics human tissue inherited cardiomyopathy mouse model novel papillary muscle plakophilin 2 sudden cardiac death targeted treatment therapeutic target transcriptome sequencing transcriptomic profiling transcriptomics

项目摘要

Abstract Arrhythmogenic cardiomyopathies are inherited or acquired abnormalities of the heart that provide substrate and triggers that initiate and sustain ventricular arrhythmias. Ventricular arrhythmias range from infrequent premature ventricular contractions (PVCs) to more concerning burdens of PVCs, which can then trigger sustained ventricular tachycardia, which even if self-terminating, are harbinger of future non-terminating VT, which can be hemodynamically unstable and fatal if not terminated by defibrillation. Diverse cellular, molecular, and environmental etiologies have been suggested to explain the pathogenesis of arrhythmogenic cardiomyopathies including fibrosis and scar, pathologic excitability of cardiomyocytes, and even influences from resident or bone marrow derived myeloid cells. We hypothesize that although arrhythmogenic cardiomyopathies have distinct origins and etiologies, they share a common set of cellular, molecular, and microenvironmental features comprising a stereotyped arrhythmogenic niche that can be targeted for therapeutic benefit. This administrative supplement to the funded R01 HL162369 entitled, “Uncovering Molecular Targets for Arrhythmogenic Cardiomyopathy Therapeutics” is focused on studying arrhythmogenic cardiomyopathy with single cell spatial resolution. The goal of this supplement is to apply these methods to dissect the cellular and molecular microenvironment of the arrhythmogenic cardiomyopathy niche in models where fibrosis serves as a substrate and conspires with electrical triggers, first in an arrhythmogenic cardiomyopathy mouse model from the funded R01 and then by comparison to heart tissue from human arrhythmogenic mitral valve prolapse (MVP), where fibrosis of the mitral valvular apparatus acts as a substrate. We aim to define: (1) the cell subsets, molecular pathways, and potential cellular communication pathways activated by mechanically-induced arrhythmogenic substrates using single cell/nuclei RNA-Seq and (2) the spatial location and organization of the mechanically- induced arrhythmogenic niche by combining structural histologic analysis with spatial transcriptomics and single cell resolution smFISH. Results generated by the proposed supplement will benefit the original arrhythmogenic cardiomyopathy-focused R01 by identifying therapeutic targets for arrhythmogenic cardiomyopathy as well as the CAROL Act goal of building dynamic risk assessment technologies and uncovering mechanisms underlying arrhythmogenic MVP.

摘要