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:
  • 金额:
    $ 81.65万
  • 依托单位:
  • 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

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

项目成果

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William Tswenching Pu其他文献

William Tswenching Pu的其他文献

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{{ truncateString('William Tswenching Pu', 18)}}的其他基金

CMYA5 regulation of cardiac dyad structure and function
CMYA5对心脏二元体结构和功能的调节
  • 批准号:
    10607816
  • 财政年份:
    2022
  • 资助金额:
    $ 81.65万
  • 项目类别:
Genetic regulation of atrial gene expression in development and disease
发育和疾病中心房基因表达的遗传调控
  • 批准号:
    10576399
  • 财政年份:
    2021
  • 资助金额:
    $ 81.65万
  • 项目类别:
Genetic regulation of atrial gene expression in development and disease
发育和疾病中心房基因表达的遗传调控
  • 批准号:
    10355481
  • 财政年份:
    2021
  • 资助金额:
    $ 81.65万
  • 项目类别:
Regulation of Cardiomyocyte Maturation
心肌细胞成熟的调节
  • 批准号:
    9888413
  • 财政年份:
    2019
  • 资助金额:
    $ 81.65万
  • 项目类别:
Regulation of Cardiomyocyte Maturation
心肌细胞成熟的调节
  • 批准号:
    10334508
  • 财政年份:
    2019
  • 资助金额:
    $ 81.65万
  • 项目类别:
Enabling mammalian in vivo forward genetic screens based on cell morphology
实现基于细胞形态的哺乳动物体内正向遗传筛选
  • 批准号:
    9754850
  • 财政年份:
    2018
  • 资助金额:
    $ 81.65万
  • 项目类别:
Transcriptional regulation of arteriovenous differentiation
动静脉分化的转录调控
  • 批准号:
    9751955
  • 财政年份:
    2017
  • 资助金额:
    $ 81.65万
  • 项目类别:
Transcriptional regulation of arteriovenous differentiation
动静脉分化的转录调控
  • 批准号:
    9376461
  • 财政年份:
    2017
  • 资助金额:
    $ 81.65万
  • 项目类别:
2015 Weinstein Cardiovaascular Development Conference
2015年韦恩斯坦心血管发展大会
  • 批准号:
    8911591
  • 财政年份:
    2015
  • 资助金额:
    $ 81.65万
  • 项目类别:
YAP1 Regulation of cardiomyocyte proliferation, function, and regeneration
YAP1 对心肌细胞增殖、功能和再生的调节
  • 批准号:
    8412652
  • 财政年份:
    2013
  • 资助金额:
    $ 81.65万
  • 项目类别:

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