Combination of Doxorubicin (Dox) and the monoclonal antibody trastuzumab (Trz) is being effectively used against breast cancer, but associated with high incidence of cardiotoxicity. The mechanisms of Dox+Trz induced synergic cardiotoxicity are still unclear. Recently the activation of the microRNA 146a has been shown to have a role in the synergistic effect of Dox and Trz cardiotoxicity. MicroRNAs (miRNA) are ~22 nucleotides long non-coding RNAs regulating complex cellular processes. MiRNAs can be detected in the systemic circulation and their levels increase under various stress conditions. Growing body of evidence suggests that circulating miRNAs are actively released and may act as signaling molecules on close or even distant target cells. Mechanism of miRNA secretion is not completely characterized Recent literature suggests a intriguing idea that the nucleolus may play a critical role during miRNA release and reuptake . The short term goal of this proposal is to identify a diagnostic signature of circulating miRNA in response to Dox+Trz treatment. The long term goal is to study the mechanisms of release and reuptake of miRNAs and demonstrate the role of the nucleolus in these processes. Specific tasks will focus on: 1) Analysis of circulating miRNAs from plasma of mice treated with Saline, Dox or Dox+Trz. 2) Identification of secreted miRNAs in response to Dox, Trz , and Dox+Trz in adult human cardiac stromal cells (hCStCs) and cardiac progenitor cells (hCPCs). 3) Study the mechanism/s of release and uptake of miRNAs upon stress. 4) Role of the nucleolar protein nucleophosmin (NPM) on miRNAs export and uptake upon stress. Significance is the delineation of new mechanisms controlling myocardial stress response and identification of molecular interventional targets that mitigate drug-mediated cardiotoxicity and improve myocardial survival.
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