Though it Is known that cardioprotection enhances myocardial survival and stem cell (SC) recruitment, whether the gene/miRNA networks involved in cardioprotection promote SC-mediated cardiac repair is unknown. Moreover, whether miRNA exert their effects primarily in myocardial cells or in injected SC, and to what extent transfer of miRNA from one cell type to another is required for cardiac repair is unknown. This critical gap in knowledge prevents development of therapeutic strategies employing manipulation of protective gene/miRNA networks and SC. The central hypothesis is that expression of protective genes and repression of apoptotic genes, mediated by the gene/miRNA network, underlies enhanced myocardial survival, improved survival and function of injected mesenchymal stem cells (MSC), and positive effects upon the heart post-MI. The rationale is that by addressing this hypothesis, we will learn which miRNAs are effective, the site and mechanism of their action. We propose two SPECIFIC AIMS; 1) Determine the role and mechanism of NF-?B-dependent microRNAs that regulate pro-survival genes in cardioprotection and MSC survival/regeneration, and 2) Determine the role and mechanism of NF-?B-dependent microRNAs regulating pro cell death genes in cardioprotection and MSC survival/regeneration. The approach is gain-and loss-of-function in cardiac cells and MSC, and in vivo, using murine models of I/R injury. Labelled RNAs and real-time video imaging will allow study of miRNA transfer from one cell to another, and the results of this at the gene expression and functional levels assessed. Cardioprotection, delivery of RNA therapeutics, and SC are being pursued in clinical trials. However, the specific combinations of these studied herein, have not been explored but are feasible. The proposed research is highly significant in that it will allow us to understand the regulatory role of miRNAs and their target genes, and to employ this knowledge in identifying therapeutic targets and developing small RNA therapeutics. This proposal is innovative in that is addresses a novel hypothesis, based upon our unique preliminary data, and incorporates the novel concept that activation of protective pathways in the myocardium will enhance survival/function of injected SC. We leverage our unique knowledge of gene/miRNA networks that result in cardioprotection for the purpose of protecting MSC in the inhospitable environment of the ischemic heart. 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.

Public Health Relevance

The proposed research is SIGNIFICANT because it will lead to identification of new therapeutic targets and development of novel therapies for ischemic heart disease. The proposal employs a novel and innovative set of reagents that can be used for RNA delivery in vivo, and is highly TRANSLATIONAL in that miRNA/gene networks are conserved and may be manipulated clinically, using RNA therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091478-08
Application #
9069016
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schwartz, Lisa
Project Start
2007-12-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Type
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Yu, Bin; Yang, Yueting; Liu, Huan et al. (2016) Clusterin/Akt Up-Regulation Is Critical for GATA-4 Mediated Cytoprotection of Mesenchymal Stem Cells against Ischemia Injury. PLoS One 11:e0151542
Haar, Lauren; Ren, Xiaoping; Liu, Yong et al. (2014) Acute consumption of a high-fat diet prior to ischemia-reperfusion results in cardioprotection through NF-?B-dependent regulation of autophagic pathways. Am J Physiol Heart Circ Physiol 307:H1705-13
Thomas, Candice M; Yong, Qian Chen; Rosa, Rodolfo M et al. (2014) Cardiac-specific suppression of NF-?B signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system. Am J Physiol Heart Circ Physiol 307:H1036-45
Rubinstein, Jack; Lasko, Valerie M; Koch, Sheryl E et al. (2014) Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance. Am J Physiol Heart Circ Physiol 306:H574-84
Lam, Chi Keung; Zhao, Wen; Cai, Wenfeng et al. (2013) Novel role of HAX-1 in ischemic injury protection involvement of heat shock protein 90. Circ Res 112:79-89
Koch, Sheryl E; Haworth, Kevin J; Robbins, Nathan et al. (2013) Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study. Ultrasound Med Biol 39:2034-43
Koch, Sheryl E; Tranter, Michael; Robbins, Nathan et al. (2013) Probenecid as a noninjurious positive inotrope in an ischemic heart disease murine model. J Cardiovasc Pharmacol Ther 18:280-9
Koch, Sheryl E; Gao, Xiaoqian; Haar, Lauren et al. (2012) Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation. J Mol Cell Cardiol 53:134-44
Tranter, Michael; Liu, Yemin; He, Suiwen et al. (2012) In vivo delivery of nucleic acids via glycopolymer vehicles affords therapeutic infarct size reduction in vivo. Mol Ther 20:601-8
Zuo, Shi; Jones, W Keith; Li, Hongxia et al. (2012) Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury. Stem Cells Dev 21:598-608

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