Nucleolar disruption in response to cardiomyopathic stress and injury

描述(申请人提供)：除了控制核糖体的生物发生，越来越多的证据表明，核仁是细胞应激的传感器，核仁破坏和P53激活对心脏毒性药物的反应就是明证。核仁蛋白核干素(NS)是在心肌损伤后诱导的，与核磷蛋白(NPM)和P53途径成员相互作用。NPM对非心肌细胞的细胞应激反应具有保护作用，并与AKT合作，介导核抗凋亡信号。这项建议的长期目标是证明核仁应激对心肌损害的贡献。短期目标是确定NS和NPM参与对抗核仁应激的机制基础。结果表明：1)NS和NPM是心脏毒性物质介导的应激感受器；2)NS和NPM对核仁应激具有保护作用；3)核仁应激能拮抗小鼠和人心脏祖细胞的增殖和衰老。实验涉及小鼠心脏保护模型、培养的心肌细胞以及来自小鼠和人类的心脏祖细胞系。核仁应激在心肌背景下仍未被探索，加强了从这些研究中获得的新颖性和知识。重要的是描述了控制心肌应激反应的新机制，以及揭示了以前未知的心脏保护信号的作用。识别分子干预靶点，以减轻药物介导的心脏毒性，改善心肌存活、增殖和修复，对于加强促进心肌挽救、修复和再生的治疗策略至关重要。 公共卫生相关性：心脏病仍然是美国的一个主要原因或发病率和死亡率，患者的长期护理和住院是国家医疗保健系统的重大负担。尽管在过去的几十年里取得了进展，但我们仍然不能真正解决心力衰竭的根本问题：收缩功能和活性组织的进行性丧失。这项建议侧重于一种新的基本分子机制，涉及保存核仁功能，以增强细胞对急性损伤、长期应激或心脏毒性药物治疗的病理损伤的抵抗力。

DESCRIPTION (provided by applicant): In addition to governing ribosomal biogenesis, a growing body of evidence indicates the nucleolus acts as a sensor of cellular stress as evidenced by nucleolar disruption and p53 activation in response to cardiotoxic agents. The nucleolar protein nucleostemin (NS), induced in response to cardiomyopathic damage, interacts with nucleophosmin (NPM) and members of the p53 pathway. NPM is protective in response to cellular stress in non-myocytes and partners with AKT to mediate nuclear antiapoptotic signaling. The long term goal of this proposal is to demonstrate the contribution of nucleolar stress to cardiomyopathic damage. The short term goal is to determine the mechanistic basis of NS and NPM involvement in antagonizing nucleolar stress. Specific aims will demonstrate: 1) NS and NPM are sensors of stress mediated by cardiotoxic agents, 2) NS and NPM protect against nucleolar stress, and 3) Nucleolar stress antagonizes proliferation and increases senescence of mouse and human cardiac progenitor cells. Experiments involve mouse models of cardioprotection, cultured cardiomyocytes and cardiac progenitor cell lines derived from mice and humans. Nucleolar stress in the myocardial context remains unexplored, reinforcing the novelty and knowledge to be gained from these studies. Significance is the delineation of new mechanisms controlling myocardial stress response together with revealing a previously unknown action of cardioprotective signaling. Identification of molecular interventional targets that mitigate drugs- mediated cardiotoxicity and improve myocardial survival, proliferation, and repair, are essential to enhance therapeutic strategies for promotion of myocardial salvage, repair, and regeneration. PUBLIC HEALTH RELEVANCE: Heart disease remains a major cause or morbidity and mortality in the United States, with long term care and hospitalization of patients a significant burden on the national health care system. Despite advances over the last several decades we are still not truly capable of addressing the fundamental issue in heart failure: the progressive loss of contractile function and viable tissue. This proposal focuses upon a novel fundamental molecular mechanism involving preservation of nucleolar function that enhances cellular resistance to pathologic injury from acute insult, long term stress, or cardiotoxic drug treatments.