This proposal describes a five-year career development program to prepare the Candidate, Dr. Ioannis Karakikes, for a career as an independent investigator. This program will build on Dr. Karakikes' background as a basic cell and molecular biologist by providing expertise in molecular cardiology and multimodality cardiac imaging methodologies. The mentor is Dr. Roger Hajjar who is Professor of Medicine and Director of the Cardiovascular Research Center at the Mount Sinai School of Medicine. The proposed mentor is an expert in cardiac physiology and cardiac gene therapy. The K99 phase will consist of structured mentorship by the primary mentor, complementary meetings with an advisory committee, formal coursework, a provocative research project and a program of career transition. In his preliminary studies, Dr. Karakikes has developed and validated a set of molecular and cell biology tools to study the potential role of microRNAs (miRNAs) in the pathogenesis of diabetic cardiomyopathy. Dr. Karakikes has identified several diabetic cardiomyopathy- associated miRNAs, however, the proposed studies will focus on the detailed characterization of miRNA-152 (miR-152). In preliminary studies, Dr. Karakikes has demonstrated that miR-152 overexpression profoundly altered glucose uptake and induced a hypertrophic response and contractile dysfunction in primary cardiomyocytes in vitro. In the research approach, Dr. Karakikes will build on these findings to test the hypothesis that miR-152 regulates cardiac contractility and ventricular remodeling in vivo. To date the Candidate has accrued the technical competencies necessary to conduct the proposed comprehensive analysis of miRNA modulated cardiac function. To address the overall goal of the project, an inducible cardiac- specific miR-152 transgenic mouse model was generated. This model will be used to phenotypically characterize the role of miRNA in cardiac function, ventricular remodeling and to determine its target genes.
In Specific Aims 1 and 2 of the K99 phase, the Candidate will assess cardiac function in miR-152 overexpressing mice using multiparametric imaging, hemodynamic and electrophysiological methodologies. These studies will be coupled with detailed histological and molecular analysis of cardiac tissue samples. During Specific Aims 3 and 4 of the R00 segment, the Candidate will use a comprehensive set of molecular approaches to identify the specific target genes for miR-152 and possible regulatory networks that mediate pathological remodeling in the diabetic heart. Dr Karakikes' ultimate goal is to use this information to develop novel therapeutic modalities for diabetes-related cardiac dysfunction. Collectively, the proposed work will elucidate novel mi-RNA-based mechanisms underlying cardiovascular function and pathophysiology. In addition, this work will provide a foundation for future studies on the role of miR-152 and other miRNAs in heart function to be eventually carried out by Dr. Karakikes as an independent investigator.

Public Health Relevance

MicroRNAs (miRNAs) are newly discovered regulators of gene expression in the heart. In this proposal we will investigate the role of miR-152 in the pathogenesis and progression of diabetic cardiomyopathy. This knowledge should ultimately be of value for understanding the etiology of the disease and they will define potential therapeutic targets for the future treatments. )

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL104002-05
Application #
9616773
Study Section
Special Emphasis Panel (NSS)
Program Officer
Shi, Yang
Project Start
2017-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Chang, Alex C Y; Chang, Andrew C H; Kirillova, Anna et al. (2018) Telomere shortening is a hallmark of genetic cardiomyopathies. Proc Natl Acad Sci U S A 115:9276-9281
Kaur, Balpreet; Perea-Gil, Isaac; Karakikes, Ioannis (2018) Recent Progress in Genome Editing Approaches for Inherited Cardiovascular Diseases. Curr Cardiol Rep 20:58
Abilez, Oscar J; Tzatzalos, Evangeline; Yang, Huaxiao et al. (2018) Passive Stretch Induces Structural and Functional Maturation of Engineered Heart Muscle as Predicted by Computational Modeling. Stem Cells 36:265-277
Chen, Caressa; Termglinchan, Vittavat; Karakikes, Ioannis (2017) Concise Review: Mending a Broken Heart: The Evolution of Biological Therapeutics. Stem Cells 35:1131-1140
Termglinchan, Vittavat; Seeger, Timon; Chen, Caressa et al. (2017) Efficient Genome Editing in Induced Pluripotent Stem Cells with Engineered Nucleases In Vitro. Methods Mol Biol 1521:55-68
Karakikes, Ioannis; Termglinchan, Vittavat; Cepeda, Diana A et al. (2017) A Comprehensive TALEN-Based Knockout Library for Generating Human-Induced Pluripotent Stem Cell-Based Models for Cardiovascular Diseases. Circ Res 120:1561-1571
Karakikes, Ioannis; Ameen, Mohamed; Termglinchan, Vittavat et al. (2015) Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circ Res 117:80-8
Karakikes, Ioannis; Stillitano, Francesca; Nonnenmacher, Mathieu et al. (2015) Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat Commun 6:6955
Karakikes, Ioannis; Termglinchan, Vittavat; Wu, Joseph C (2014) Human-induced pluripotent stem cell models of inherited cardiomyopathies. Curr Opin Cardiol 29:214-9