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首页> 外文学位 >Deletion of the Chromatin Remodeling Factor Brg1 Leads to Genomic Instability During Development, and Confers Sensitivity to Adult-onset Doxorubicin Cardiotoxicity in Mice.
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Deletion of the Chromatin Remodeling Factor Brg1 Leads to Genomic Instability During Development, and Confers Sensitivity to Adult-onset Doxorubicin Cardiotoxicity in Mice.

机译：染色质重塑因子Brg1的删除导致发育过程中的基因组不稳定，并赋予小鼠成年发作的阿霉素心脏毒性敏感性。

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摘要

Cardiovascular disease is the number one killer of adults in the United States. Paradoxically, a certain subtype of the most prevalent morbidity and mortality factor (heart disease) is due to treatment for the second most prevalent morbidity and mortality factor (cancer): this is the case for doxorubicin cardiotoxicity. Doxorubicin continues to be an efficacious treatment for a variety of solid and hematopoietic liquid tumors, and as such receives continued clinical use. Cardiac toxicity is an under-recognized side effect of several biopharmaceutical and environmental chemical agents. The degree of toxicity may be mediated by epigenetic events, such as chromatin remodeling. It is known the chromatin remodeling factor Brg1, a catalytic subunit of the SWI/SNF ATPase chromatin remodeling complex, is required in cardiovascular development and pathologic cardiac hypertrophy. However, BRG1 necessity during development beyond certain embryonic stages has not been fully investigated, nor has its potential role in doxorubicin cardiotoxicity. Due to the known chromatin remodeling activities of BRG1, the requirement of Brg1 during early embryonic development and its role in the response to cardiotoxicity caused by doxorubicin was investigated. BRG1 ablation beginning at E6.5 results in arrested growth and embryonic death by E9.5 due to developmental defects. Microarray analysis revealed BRG1's role in maintaining genomic integrity, without which there is aberrant expression of cell cycle, proliferation, and apoptosis pathways leading to the observed pathologic phenotype. This demonstrates that BRG1's role in genomic surveillance is essential for survival after the pre-implantation period for normal cellular proliferation and differentiation. Adult Brg1 WT and Brg1 KO mice were subjected to a doxorubicin regimen with repeated dosing over several weeks, analogous to repeat-dose paradigms used in the human clinical setting. Analyses of tissues including protein and RNA biochemistry, microarray analysis, serum biochemistry, and light and electronic microscopic analyses confirmed the presence of doxorubicinassociated lesions in treated mice; however, morphologically-similar lesions were also observed at a lesser incidence and severity in untreated Brg1 KO mice. Microarray analysis revealed significant differentially expressed genes with common clustering between both the treated groups and the Brg1 KO groups, suggesting both common and dissimilar molecular mechanisms between Brg1 KO-induced cardiomyocyte lesions and those induced by doxorubicin treatment. This analysis additionally identified differentially expressed genes previously unreported to be associated with doxorubicin cardiotoxicity. The work in this dissertation has revealed that not only is Brg1 required for the maintenance of normal cardiomyocyte homeostasis during development, but found that despite previous reports it is required in adulthood as well. Furthermore, its absence has common and dissimilar mechanisms to that suffered from treatment with doxorubicin, suggesting mechanisms unique to Brg1 knockout irrespective of treatment may reveal new pathways for therapeutic targeting in patients at risk for doxorubicin cardiotoxicity.
机译：心血管疾病是美国成年人的头号杀手。矛盾的是，某种最普遍的发病率和死亡率因子（心脏病）的亚型是由于治疗第二最普遍的发病率和死亡率因子（癌症）所致：阿霉素心脏毒性就是这种情况。阿霉素仍然是治疗各种实体和造血性液体肿瘤的有效方法，因此得到了持续的临床应用。心脏毒性是几种生物制药和环境化学试剂的未充分认识到的副作用。毒性程度可能由表观遗传事件（例如染色质重塑）介导。众所周知，染色质重塑因子Brg1是SWI / SNF ATPase染色质重塑复合体的催化亚基，是心血管发展和病理性心脏肥大所必需的。然而，BRG1在某些胚胎阶段以外发育的必要性尚未得到充分研究，其在阿霉素心脏毒性中的潜在作用也未得到充分研究。由于已知的BRG1染色质重塑活性，研究了Brg1在早期胚胎发育过程中的需求及其在阿霉素引起的心脏毒性反应中的作用。从E6.5开始的BRG1切除会由于发育缺陷而导致E9.5停滞的生长和胚胎死亡。基因芯片分析揭示了BRG1在维持基因组完整性中的作用，如果没有基因组完整性，则细胞周期，增殖和凋亡途径的异常表达会导致观察到的病理表型。这表明BRG1在基因组监测中的作用对于正常细胞增殖和分化的植入前期后的存活至关重要。成年的Brg1 WT和Brg1 KO小鼠接受阿霉素治疗，并在数周内重复给药，类似于在人类临床环境中使用的重复剂量范例。对组织的分析包括蛋白质和RNA生物化学，微阵列分析，血清生物化学以及光学和电子显微镜分析，证实在治疗的小鼠中存在阿霉素相关的病变。但是，在未经治疗的Brg1 KO小鼠中，形态相似的病变的发生率和严重性也较低。基因芯片分析显示，在治疗组和Brg1 KO组之间存在显着差异表达的基因，具有共同的簇集，这表明Brg1 KO诱导的心肌细胞损伤与阿霉素诱导的心肌细胞损伤之间的共同分子机制和相异分子机制。该分析还鉴定了以前未报道与阿霉素心脏毒性有关的差异表达基因。本论文的工作表明，Brg1不仅在发育过程中维持正常的心肌细胞稳态需要，而且发现，尽管有以前的报道，成年期也需要。此外，它的缺乏与阿霉素治疗的机制具有共同的和不同的机制，这表明不管治疗如何，Brg1基因敲除所独有的机制都可能为具有阿霉素心脏毒性风险的患者提供靶向治疗的新途径。

著录项

  • 作者

    Boyle, Michael Christopher.;

  • 作者单位

    North Carolina State University.;

  • 授予单位 North Carolina State University.;
  • 学科 Pathology.;Molecular biology.;Genetics.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 175 p.
  • 总页数 175
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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