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.
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.
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