Mechanisms and Therapeutic Targeting of DNA Damage in Dilated Cardiomyopathy Caused by LMNA Mutations

LMNA 突变引起的扩张型心肌病 DNA 损伤的机制和治疗靶点

基本信息

  • 批准号:
    10684002
  • 负责人:
  • 金额:
    $ 48.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-03-15 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Mutations in the LMNA gene, encoding lamin A/C (LMNA) protein, cause a diverse array of diseases referred to as laminopathies. Dilated cardiomyopathy (DCM) is common and the main cause of death in laminopathies. LMNA mutations are also the second most common causes of familial DCM. DCM due to LMNA mutations (hereafter, LMNA-DCM) has a poor prognosis and a high incidence of sudden cardiac death. The underpinning mechanism(s) of LMNA-DCM is unknown. Hence, there is no effective therapy for LMNA-DCM. We have shown that LMNA binds to about 300 genomic regions in human cardiac myocytes, which are referred to as Lamin-Associated Domains (LADs). LADs comprise about 20% of the genome and several hundred genes. We show that LADs are redistributed in LMNA-DCM, resulting in Gain of LADs (GoL) and Loss of LADs (LoL). LoL is associated with active transcription, whereas GoL suppresses gene expression. At the mechanistic level, Preliminary data show that LADs are lost at the binding motifs for CTCF protein. CTCF insulates transcriptionally active chromatin loops and recruits topoisomerase 2B (TOP2B) to cut the compact chromatin and open the loops for active transcription. In parallel with these findings, we show that double stranded DNA breaks (DSBs), induced by TOP2B, are increased. We also show that expression of DSB repair genes is suppressed in LMNA-DCM, partly because of GoL. Consequently, DSBs are released into the cytoplasm and sensed by CGAS protein, which activates DNA damage response (DDR) and expression of genes involved in cell death, senescence, fibrosis, and cardiac dysfunction, phenotypic features of human LMNA-DCM. We propose to study the mechanisms responsible for increased DSBs and impaired DSB repair, and determine therapeutic effects of targeting the DDR pathway in LMNA-DCM. In aim 1, we will test the hypothesis that LoL leads to active transcription, induction of DSBs, and stalled TOP2B, whereas GoL suppresses transcription (hence, no DSBs). To test this hypothesis, we will map genome-wide DSB sites at the nucleotide level by END-Seq technique, compare distribution density of DSBs at LoL, GoL, and non-LAD regions in control and LMNA-DCM hearts, and determine stalling of TOP2B at the DSBs by ChIP-Seq. In aim 2, we will test the hypothesis that DSB repair is impaired in LMNA-DCM partly because GoL suppresses expression of key repair genes and in. part because recruitment of the repair enzymes to the DSB sites is impaired. Recruitment and assembly of the selected repair proteins at the DSBs will be analyzed by ChIP-Seq to map the binding motifs to DSB sites. Interactions between LMNA and the repair proteins will be determined by immunoprecipitation. In aim 3, the DDR pathway will be blocked genetically and pharmacologically by inhibiting CGAS, the key sensor of the cytoplasmic DNA, in two mouse models of LMNA-DCM. The ensuing effects on survival, cardiac function, gene expression, DDR activation, fibrosis, senescence, and apoptosis will be determined. The findings could delineate the mechanisms of increased DSBs and determine therapeutic effects of targeting of the DDR in LMNA-DCM.
编码层蛋白A/C(LMNA)的LMNA基因突变会导致多种疾病 称为椎板病症。扩张型心肌病(DCM)是一种常见的心肌病,是 椎板病症。LMNA突变也是家族性DCM的第二大常见原因。由LMNA引起的DCM 突变(以下简称LMNA-DCM)预后差,心脏性猝死发生率高。这个 LMNA-DCM的支撑机制(S)尚不清楚。因此,LMNA-DCM尚无有效的治疗方法。 我们已经证明LMNA结合到人类心肌细胞中大约300个基因组区域,这些区域是 称为与LAMIN相关的域(LADS)。LAD约占基因组的20%,并有几个 上百个基因。我们发现,在LMNA-DCM中,LADS被重新分配,导致LADS的增益(GOL)和损失 小伙子们(哈哈)。LOL与活跃的转录有关,而GOL抑制基因表达。 在机制水平上,初步数据显示LADs在CTCF蛋白的结合基序上丢失。 CTCF隔离转录活性染色质环并招募拓扑异构酶2B(TOP2B)来切割 紧凑染色质并打开环路以进行活跃的转录。在这些发现的同时,我们表明 TOP2B诱导的双链DNA断裂(DSB)增加。我们还给出了DSB表示 修复基因在LMNA-DCM中被抑制,部分原因是GOL。因此,DSB被释放到 细胞质,并被cGAS蛋白感知,激活DNA损伤反应(DDR)和基因表达 参与细胞死亡、衰老、纤维化和心脏功能障碍,人类LMNA-DCM的表型特征。 我们建议研究导致DSB增加和DSB修复受损的机制,以及 确定靶向DDR通路在LMNA-DCM中的治疗效果。在目标1中,我们将检验假设 LOL导致活跃的转录、DSB的诱导和TOP2B的停滞,而GOL抑制 转录(因此,没有DSB)。为了验证这一假设,我们将在核苷酸上绘制全基因组的DSB位置图 逐级末端序列技术,比较对照中DSB在LOL、GOL和非LAD区域的分布密度 和LMNA-DCM心脏,并用芯片序列测定TOP2B在DSB的失速。在目标2中,我们将测试 假设LMNA-DCM中DSB修复受损的部分原因是GOL抑制关键修复的表达 基因和基因。部分原因是修复酶在DSB部位的募集受到损害。招聘和 选择的修复蛋白在DSB上的组装将通过CHIP-SEQ进行分析,以将结合基序映射到 DSB站点。LMNA和修复蛋白之间的相互作用将通过免疫沉淀来确定。在AIM 3,DDR途径将通过抑制cGAS从基因和药物上被阻断,cGAS是 在两种LMNA-DCM小鼠模型中,胞浆DNA。对生存、心功能、基因的后续影响 将确定其表达、DDR激活、纤维化、衰老和细胞凋亡。这些发现可以描绘出 探讨DSB升高的机制,确定靶向DDR治疗LMNA-DCM的疗效。

项目成果

期刊论文数量(50)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes.
  • DOI:
    10.1161/circresaha.117.311876
  • 发表时间:
    2017-12-08
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Karmouch J;Zhou QQ;Miyake CY;Lombardi R;Kretzschmar K;Bannier-Hélaouët M;Clevers H;Wehrens XHT;Willerson JT;Marian AJ
  • 通讯作者:
    Marian AJ
Highlights of American Heart Association Scientific Sessions 2020: a virtual experience.
  • DOI:
    10.1093/cvr/cvaa346
  • 发表时间:
    2021-01-01
  • 期刊:
  • 影响因子:
    10.8
  • 作者:
    Adão R;Marian AJ
  • 通讯作者:
    Marian AJ
Editors' Preamble to The Journal of Cardiovascular Aging.
《心血管衰老杂志》编辑序言。
  • DOI:
    10.20517/jca.2021.01
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Marian,AliJ;Asatryan,Babken;Bolli,Roberto;Cheedipudi,SirishaM;Dhalla,NaranjanS;Finkel,Toren;Frangogiannis,NikolaosG;Gurha,Priyatansh;Belmonte,JuanCarlosIzpisua;Hare,JoshuaM;Hong,Kui;Kirshenbaum,LorrieA;Lee,RichardT;Leesa
  • 通讯作者:
    Leesa
Sporadic dilated cardiomyopathy is often familial.
散发性扩张型心肌病通常具有家族性。
  • DOI:
    10.1093/cvr/cvac075
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    10.8
  • 作者:
    Marian,AliJ
  • 通讯作者:
    Marian,AliJ
Non-syndromic cardiac progeria in a patient with the rare pathogenic p.Asp300Asn variant in the LMNA gene.
LMNA 基因中存在罕见致病性 p.Asp300Asn 变异的患者出现非综合征性心脏早衰症。
  • DOI:
    10.1186/s12881-017-0480-x
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Marian,AliJ
  • 通讯作者:
    Marian,AliJ
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Ali J Marian其他文献

Editorial: Gene-based renaming of human diseases.
社论:基于基因的人类疾病重命名。

Ali J Marian的其他文献

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{{ truncateString('Ali J Marian', 18)}}的其他基金

Cytosolic DNA is the Link Between Genomic Instability and Cardiovascular Aging
细胞质 DNA 是基因组不稳定性与心血管衰老之间的联系
  • 批准号:
    10722123
  • 财政年份:
    2023
  • 资助金额:
    $ 48.39万
  • 项目类别:
Cell type-Specific Therapeutic Targeting of canonical WNT Pathway in Arrhythmogenic Cardiomyopathy
致心律失常性心肌病典型 WNT 通路的细胞类型特异性治疗靶向
  • 批准号:
    10594529
  • 财政年份:
    2020
  • 资助金额:
    $ 48.39万
  • 项目类别:
Cell type-Specific Therapeutic Targeting of canonical WNT Pathway in Arrhythmogenic Cardiomyopathy
致心律失常性心肌病典型 WNT 通路的细胞类型特异性治疗靶向
  • 批准号:
    10418626
  • 财政年份:
    2020
  • 资助金额:
    $ 48.39万
  • 项目类别:
Pathogenic Role of Selected Cardiac Myocyte- and Fibroblast-Specific Epigenetic Changes in Laminopathies
选定的心肌细胞和成纤维细胞特异性表观遗传变化在核纤层蛋白病中的致病作用
  • 批准号:
    9242688
  • 财政年份:
    2016
  • 资助金额:
    $ 48.39万
  • 项目类别:
Mechanisms and Therapeutic Targeting of DNA Damage in Dilated Cardiomyopathy Caused by LMNA Mutations
LMNA 突变引起的扩张型心肌病 DNA 损伤的机制和治疗靶点
  • 批准号:
    10221032
  • 财政年份:
    2016
  • 资助金额:
    $ 48.39万
  • 项目类别:
Mechanisms and Therapeutic Targeting of DNA Damage in Dilated Cardiomyopathy Caused by LMNA Mutations
LMNA 突变引起的扩张型心肌病 DNA 损伤的机制和治疗靶点
  • 批准号:
    10455102
  • 财政年份:
    2016
  • 资助金额:
    $ 48.39万
  • 项目类别:
Pathogenic Role of Selected Cardiac Myocyte- and Fibroblast-Specific Epigenetic Changes in Laminopathies
选定的心肌细胞和成纤维细胞特异性表观遗传变化在核纤层蛋白病中的致病作用
  • 批准号:
    9119644
  • 财政年份:
    2016
  • 资助金额:
    $ 48.39万
  • 项目类别:
Hypertrophy Regression with N-Acetylcysteine in Hypertrophic Cardiomyopathy
N-乙酰半胱氨酸治疗肥厚型心肌病的肥厚消退
  • 批准号:
    8403983
  • 财政年份:
    2012
  • 资助金额:
    $ 48.39万
  • 项目类别:
Hypertrophy Regression with N-Acetylcysteine in Hypertrophic Cardiomyopathy
N-乙酰半胱氨酸治疗肥厚型心肌病的肥厚消退
  • 批准号:
    8240317
  • 财政年份:
    2012
  • 资助金额:
    $ 48.39万
  • 项目类别:
Hypertrophy Regression with N-Acetylcysteine in Hypertrophic Cardiomyopathy
N-乙酰半胱氨酸治疗肥厚型心肌病的肥厚消退
  • 批准号:
    8590218
  • 财政年份:
    2012
  • 资助金额:
    $ 48.39万
  • 项目类别:

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研究组蛋白乙酰化在基因组组织和白血病发生中的功能
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