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Desmosomes in cardiomyocyte homeostasis and disease

桥粒在心肌细胞稳态和疾病中的作用

基本信息

批准号：
10606894
负责人：
William Tswenching Pu
金额：
$ 81.65万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2022-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606894
关键词：
ATAC-seq Ablation Acceleration Adhesives Adipose tissue Adult Arrhythmia Biomedical Engineering Cardiac Cardiac Myocytes Cardiomyopathies Cell Nucleus Cells Chemicals Complex DISC components Data Desmosomes Development Disease Dissection Elements Experimental Models Fluorescent in Situ Hybridization Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Heart Abnormalities Heart failure Homeostasis Human In Situ Hybridization Intercalated disc Knowledge Lead Life Link Metabolism Methods Modeling Molecular Mus Muscle function Mutation Myocardial Contraction Myocardial dysfunction Myocardium N-Cadherin Pathogenesis Pathway interactions Patients Periodicity Phenotype Plasma Proteins Proteomics Regulatory Element Relaxation Resolution Role Sarcomeres Signal Transduction Testing Ventricular Arrhythmia WNT Signaling Pathway arrhythmogenic cardiomyopathy candidate identification candidate selection defined contribution desmoplakin follow-up gain of function genetic approach heart rhythm improved in vivo induced pluripotent stem cell inhibitor innovation insight loss of function mosaic multiple omics mutant novel preservation protein function single molecule single nucleus RNA-sequencing transcriptome transcriptomics

项目摘要

SUMMARY Intercalated disks (ICDs) connect the termini of adjacent cardiomyocytes (CMs) physically, electrically, and chemically. The structural role of ICDs to preserve CM integrity in the face of billions of cycles of forceful con- traction and relaxation is well appreciated; however, the function of ICDs as essential CM signaling hubs is only now emerging. Arrhythmogenic cardiomyopathy (ACM) provides a unique window into the function of ICDs and specifically desmosomes. ACM is a potentially lethal disorder characterized by high arrhythmia bur- den, loss of contractile myocardium, and replacement by fibro-fatty tissue. Mutations of desmosome genes (PKP2, DSG2, DSC2, DSP, JUP) occur in approximately half of ACM patients. Despite growing knowledge about ACM disease pathogenesis, the mechanistic links between desmosome mutations and arrhythmias, my- ocardial dysfunction, and fibrofatty replacement remain poorly understood. The overall goal of this proposal is to gain insights into the mechanisms by which desmosome mutations cause arrhythmia and myocardial dysfunction; Our overarching hypothesis is that desmosomes are inte- gral for maintaining normal cardiomyocyte homeostasis through both their structural and signaling activities. ACM mutations disrupt these activities to cause both loss of structural integrity and aberrant signaling. We will test these hypotheses through four parallel but complementary Specific Aims: (1) We will examine cell composition and gene regulation of human ACM myocardium, using concurrent single nucleus RNA-seq and ATAC-seq, and spatial transcriptomics (snMulti-seq) with massively parallel single molecule fluo- rescent in situ hybridization (MERFISH); (2) We will use mosaic, adult, cardiomyocyte specific inactivation of Dsp to probe the cell autonomous functions of desmosomes. This model will be studied using snMulti-seq and MERFISH, followed by interrogation of key predicted regulators using in vivo gain- and loss-of-function ap- proaches; (3) Using proximity proteomics of ICD component N-cadherin, we identified novel ICD components and ICD components that are altered by Dsp ablation. We will use in vivo gain- and loss-of-function ap- proaches to study the function of selected candidates identified by this screen; (4) Define the contributions of WNT and GSK3 signaling to ACM phenotypes in DSP mutant hiPSC-CMs. Using genetic approaches in bioen- gineered hiPSC-CMs, we will dissect the involvement of GSK3 and WNT signaling to ACM pathogenesis. Impact: This proposal will advance our understanding of the function of desmosomes and ICDs in CM homeostasis and the molecular pathogenesis of ACM. This knowledge will accelerate efforts to develop targeted ACM therapies.

总结