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MicroRNA Mediated Proliferation of Adult Cardiomyocytes to Regenerate Ischemic Myocardium

Pandey, Raghav
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124343198575

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Cardiovascular diseases have been the biggest killer in the United States for decades. Despite tremendous research and new innovations, these trends do not seem to be slowing down, with more than 1 in every 3 deaths related to cardiovascular disease in 2016. In the U.S. cardiovascular diseases affect close to 92.1 million people, causing 807,775 deaths each year. According to the American Heart Association statistics report update of 2016, 17.3 million deaths worldwide were attributed to cardiovascular diseases. Moreover, this number is estimated to rise to more than 23.6 million by the year 2030. In addition, U.S. healthcare cost associated with cardiovascular disease has been rising with a massive $316 billion of associated direct and indirect cost, which is estimated to rise to $918 billion by the year 2030. Moreover, as the average age of the U.S. population increases this trend will most likely stay the same, if not increase. Etiologically, lack of oxygen and blood to the heart tissue is one the major cause of this ischemic injury and scar formation. This happens through the buildup of plaque in the arteries which reduces the blood flow and when left untreated can shut down the blood supply to downstream tissue. Our current medical approaches to deal with ischemic injuries include blood thinners, stents, beta-blockers, and surgical cleaning of the plaque. Although, heart transplants are the most optimal treatment, unavailability of donor hearts still remains a major concern when dealing with this problem. While microRNAs were first discovered in early 1990s by Ambros in C. elegans it was not until mid-2000s that first cardiac microRNA was discovered and studied. Binding to the 3’UTR (untranslated region) and inhibiting expression of the gene is the canonical mode of action for microRNAs, however there have been reports of 5’UTR binding and other non-canonical modes of action. Recent work by Matkovich et al. 2013 even determined miRNAs regulating other cardiac miRNAs. In addition to their discovery, microRNAs were shown to be differentially regulated in diseased and non-diseased cases. In addition, work by Eulalio et al. 2012 was one of the first to show miRNAs inducing proliferation in cardiomyocytes and inducing regeneration of lost myocardium, post injury. In this work, we have furthered the understanding of miRNAs and cardiovascular disease (specifically myocardial infarction) by showing a significant proliferation in adult cardiomyocytes both ex-vivo and in-vivo, which reduces infarction size and improves heart function as early as one month post treatment. We also confirmed the effect across different species (mice, rats, and human) and showed that miR1825 can induce significant proliferation in all three species. Lastly, we project a very high translational potential for this work due to the nature of miRNAs as a therapeutic: readily available, longer shelf-life, and no prerequisite for an autologous donor.
Rafeeq Habeebahmed, Ph.D. (Committee Chair)
Joshua Benoit, Ph.D. (Committee Member)
Chunying Du, Ph.D. (Committee Member)
Sohaib Khan, Ph.D. (Committee Member)
Jerry Lingrel, Ph.D. (Committee Member)
Jack Rubinstein, M.D. (Committee Member)
140 p.
Biology
Cardiomyocytes; Cardiac regeneration; microRNAs; Heart disease; Cardiovascular; Cardiovascular diseases

Recommended Citations

Citations

  • Pandey, R. (2017). MicroRNA Mediated Proliferation of Adult Cardiomyocytes to Regenerate Ischemic Myocardium [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124343198575

    APA Style (7th edition)

  • Pandey, Raghav. MicroRNA Mediated Proliferation of Adult Cardiomyocytes to Regenerate Ischemic Myocardium. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124343198575.

    MLA Style (8th edition)

  • Pandey, Raghav. "MicroRNA Mediated Proliferation of Adult Cardiomyocytes to Regenerate Ischemic Myocardium." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124343198575

    Chicago Manual of Style (17th edition)

ucin1505124343198575
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This open access ETD is published by University of Cincinnati and OhioLINK.