Role of KLF15 in Circadian Regulation of Cardiac Ischemia

Baylor College Of Medicine, Houston TX

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Abstract

? DESCRIPTION (provided by applicant): Cardiovascular diseases are the leading cause of morbidity and mortality in the U.S. It has long been documented that the incidence and severity of myocardial infarction has a diurnal variation, with the peak in the early morning. The molecular basis, however, is poorly understood. Also, state-of-the-art flow restoring therapies cannot avoid the ischemic reperfusion (I/R) injury either at the time of heart attack or during revascularization. Kruppel-like zinc finger transcription factors play important roles in multiple aspects of cardiovascular biology. We have characterized the role of Kruppel-like factor 15 (KLF15) in regulating cellular metabolism in the liver and the skeletal muscle. Nascent observations by the applicant suggest a critical role of KLF15 in coordinating catabolism and reactive oxygen species (ROS) clearance in the heart. KLF15 deficient myocardium/cardiomyocytes exhibits increased accumulation of ROS and exaggerated susceptibility to I/R injury. Using next generation sequencing, we discovered that KLF15 governs 75% of the oscillating transcripts in the heart and organize them into two temporal functional clusters, one enriched for catabolic genes coincides with the active phase, another enriched for remodeling and repair genes coincides with the resting phase. Loss of function of KLF15 in the murine heart leads to aberrant oscillation. Finally, KLF15 is significantly reduced in human heart samples with ischemic cardiomyopathy. Using a combination of murine models and molecular/cellular approaches, Dr. Zhang will study the molecular mechanisms of cardiac KLF15 in the dynamic process circadian regulation of fuel utilization and redox homeostasis. In addition, Dr. Zhang will use novel induced pluripotent stem cell derived cardiomyocyte (iPS-CM) technology to extend the studies to human cells. With the support provided by the K08 award, Dr. Zhang's project will lead to a better understanding of the role of KLF15 on the circadian variability of the susceptibility to I/R injury, reveal the molecular mechanism of such regulation and may provide a foundation for the development of novel therapies to limit myocardial injury. The specific aims of the proposal include: 1. To determine the effect of KLF15 deficiency on cardiac I/R injury: We will use cardiac-specific KLF15 KO mice to assess the cardiac I/R injury, lipid metabolism, ROS and transcriptome in a circadian fashion. 2. To identify and validate key targets of KLF15 in the cardiac circadian gene regulation: We will ChIP-seq to identify direct KLF15 targets and validate them in murine models both in vitro and in vivo. 3. To evaluate the function of KLF15 and its key targets in hiPS-CM: We will assess key findings in murine models in human iPS-CM. The applicant, Dr. Lilei Zhang, a physician-scientist with special interest in cardiogenetics, outlines a 5-year mentored career plan that will build upon her experience in human genetics, molecular biology and clinical medical genetics. Under the guidance of Dr. Mukesh Jain, a recognized leader in transcriptional and cardiovascular biology, Dr. Zhang will use tissue specific murine model combined with genomic tools to study the role of KLF15 in circadian regulation of cardiac metabolism and reduction-oxidation (redox) homeostasis. With assistance from Dr. Anthony Wynshaw-Boris, she will also use (iPS-CM) technology to extend the project to the relevant cell types in human. Dr. Zhang will be mentored by an Advisory Committee composed of highly successful, NIH-funded physician scientists at Case Western Reserve University (CWRU) with expertise in her area of research. This plan is ideally carried out in the Cardiovascular Research Institute (CVRI) at Case Western Reserve University with its distinguished record for training physician-scientists in a rich and collaborative environment. The mentored K08 award will directly advance her scientific development by protecting her effort toward her research project and help her transition into an independent investigator with her own laboratory and R01 funding.