microRNA mediation of Endothelial Progenitor Cell function in Myocardial Ichemia


Principal Investigator: Prasanna Krishnamurthy
Abstract: DESCRIPTION (provided by applicant): Animal and preliminary human studies of adult stem cell therapy for myocardial repair have shown an overall improvement of cardiac function. However, repair of injured myocardium remains a serious challenge. Emerging evidence from in vitro and preclinical studies suggests that ischemic environment including inflammation and oxidative stress, have adverse effects on stem cell function. MicroRNAs (miRNA;20-25 nucleotides), are known to regulate several cellular processes such as proliferation, differentiation, cell metabolism, apoptosis and angiogenesis. The premise of our proposed research is based on preliminary observations that 1) prolonged inflammation impairs tube formation ability of mouse BM-derived EPCs, in vitro 2) miRNA array data from EPCs, in response to inflammatory stimuli, indicates an up-regulation of number of miRNAs related to cell survival/death and angiogenesis with a robust increase in miR-377, 3) myocardial infarction (MI) increased miR-377 expression in the myocardium, circulating EPCs and plasma, 3d post-MI;4) pre-miR-377 transfection in EPCs inhibits protein expression of STK35 (a novel kinase localized in the nucleus), a potential target gene of miR-377, 5) miR- 377-mimics reduced EPC migration and vascular tube formation 6) Furthermore, STK35-knockdown in EPCs reduced HDAC5 phosphorylation and increased GATA2 acetylation (indicating transcriptional repression) and was associated with reduced expression of cytokines and growth factors, and reduced migration and vascular tube formation. 7) Most interestingly, in mouse MI model, intramyocardial transplantation of ex vivo anti-miR-377- transfected EPCs decreased cardiomyocyte apoptosis and infarct size, enhanced neovascularization and LV function and therefore efficient myocardial repair. These data provide convincing evidence that anti-miR-377 therapy might enhance the EPC engraftment and function in myocardial ischemia leading to efficient myocardial repair. Our central hypothesis is that ex vivo miR-377 knockdown and intramyocardial transplantation of EPCs augments their function by stimulating STK35-dependent phosphorylation and nuclear export of HDAC5 leading to increased GATA2-mediated transcription of genes (including cytokines and growth factors) that promote neovascularization and cardiomyocyte viability, thus resulting in efficient myocardial repair after injury. The hypotheses will be tested under the following 3 specific aims: 1) Define the role of miR-377 in EPC biology and function, in vitro 2) Elucidate the molecular mechanisms by which miR-377 regulates STK35-mediated EPC function and 3) Determine the critical role of miR-377 in EPC-mediated myocardial repair, using a mouse model of myocardial infarction.
Funding Period: 2013-08-01 - 2018-07-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. MicroRNA as mediators of angiogenesis &ischemic myocardial repair
    Meifeng Xu; Fiscal Year: 2013
    ..These findings may not only highlight the molecular mechanisms of MSCGATA-4 - mediated angiogenesis, but may also help formulate a novel therapeutic strategy for ischemia and offer insight into the progression of myocardial remodeling. ..
  2. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  3. Ca2+ Regulation in Newly Formed Ventricular Myocytes
    Steven R Houser; Fiscal Year: 2013
    ..Our preclinical studies in animal models will apply these strategies to determine if they might be useful for treating patients with many different forms of cardiac injury. ..
  4. iPS cells-derived progenitor cells for angiomyogenesis
    Yigang Wang; Fiscal Year: 2013
    ..These studies will provide new insights into the development of engineered iPSC-derived cardiac tissue patches as a viable therapy for cardiac muscle regeneration. ..
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  6. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  7. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  8. Wnt11 signaling in stem cell survival and cardiac regeneration
    Meifeng Xu; Fiscal Year: 2013
    ..The resultant secretory factors and miRNAs will allow directed differentiation and survival. These data will have far- reaching impact upon understanding of Wnt11 mediated signaling pathway in cardiac repair. ..
  9. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  10. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  11. PDE5A Inhibition Stimulates Stem Cell Survival &Differentiation
    Muhammad Ashraf; Fiscal Year: 2013
    ..The proposed study using the PDE5A inhibitors may identify a potential therapeutic role for these compounds for stem cell based de novo myocardial regeneration. ..
  12. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  13. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  14. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  15. Enhancing the effectiveness of human cardiac stem cell therapy
    Chuanxi Cai; Fiscal Year: 2013
    John M Canty; Fiscal Year: 2013
    ..The results will identify the stem cell and pathological sub- strate most likely to benefit patients with asymptomatic LVSD before clinical heart failure develops. ..
  17. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  18. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  19. Regulation of myocardial growth and death by GSK-3
    Junichi Sadoshima; Fiscal Year: 2013
    ..The knowledge obtained from this investigation should be useful for the development of better treatment for heart failure, ischemic injury and stem cell therapy. ..
  20. Function and Integration of Stem Cell-derived Cardiac Tissue Patch
    Nenad Bursac; Fiscal Year: 2013
    ..The knowledge obtained in this project will allow us to pursue in the future engineering of a functional cardiac tissue patch made of human stem cells for potential clinical applications. ..
  21. Molecular Mechanisms of Stem Cell Engraftment
    ..Insights developed from this grant could provide a significant translational advance in the new area of cell-based therapy. ..
  22. NF-kB-dependent miRNAs in Cardioprotection and Regeneration
    W Keith Jones; Fiscal Year: 2013
    ..Other novel aspects are, investigation of the role played by miRNA transfer from cell-to-cell, and use of an innovative non-viral in vivo transfection technology for small RNAs. ..
  23. Novel Therapies for Muco-Obstructive Lung Diseases
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  24. Cardiac Regeneration through Growth Factor Eluting Microrod Scaffolds
    Paul H Goldspink; Fiscal Year: 2013