Targeting Excitation-Transcription Coupling for Managing Hypertensive Cardiomyopathy
Gunther Marsche, Otto Loewi Research Center (for Vascular Biology, Immunology and Inflammation)/Senka Holzer, Department of Internal Medicine
PD Dr. Gunther Marsche|
Dr. Senka Holzer
|Availability:||This position is available.|
Medical University of Graz
|Application deadline:||Applications are accepted between February 10, 2020 00:00 and March 30, 2020 23:59 (Europe/Zurich)|
Background: Hypertensive cardiomyopathy or pathophysiological changes in myocardial structure and function caused by hypertension is a growing clinical problem due to the ageing population and a lack of curative therapies. The onset of the disease is often clinically silent, progressing over time to therapy-resistant symptomatic forms. Existing therapeutic concepts are, therefore, symptom-oriented and tailored for advanced stages of cardiac remodeling. Understanding molecular processes driving early hypertension-induced changes may improve diagnosis and treatment options.
Recent evidence positions changes in Ca2+ cycling as an early promoter of cardiac remodeling via Ca2+-mediated regulation of transcription. The enzyme Ca2+/calmodulin-dependent protein kinase II (CaMKII) has a central role in this process, as it can translate fine changes in Ca2+ fluxes into altered gene expression. However, the specific regulation of this so-called excitation-transcription coupling in hypertensive cardiomyopathy is unclear.
Hypothesis and Objectives:
This project aims to provide a comprehensive, in-depth characterization of the CaMKII-mediated transcription in hypertensive cardiomyopathy at the molecular, cellular and whole organism level. We will follow the hypothesis that (1) changes in Ca2+-mediated transcriptional activity are causally involved in the initiation and progression of hypertensive cardiomyopathy and (2) heart-specific targeting of the altered transcription via inhalation of CaMKII inhibitory peptide-loaded nanoparticles can halt disease progression or even delay its manifestation.
Methodology: We will primarily employ various techniques for assessing cardiac structure and function in vivo (blood pressure and hemodynamic pressure-volume measurements, transthoracic echocardiography) and in vitro (isolation of adult ventricular myocytes, subcellular Ca2+ imaging, purification of cardiomyocyte nuclei, electron microscopy, protein detection assays and immunofluorescence).
With our multidisciplinary approach, a wide range of state-of-the-art techniques and invaluable access to human myocardium, we expect to acquire better understanding of hypertension-related cardiac pathophysiology and provide the necessary preclinical evidence to support future translational and clinical studies employing peptide-loaded nanocarriers as a remedy for treating cardiomyopathies of different etiologies.
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- Mishra S, Gray CB, Miyamoto S, Bers DM, Brown JH. Location matters: clarifying the concept of nuclear and cytosolic CaMKII subtypes. Circ Res. 2011 Dec 9;109(12):1354-62. doi: 10.1161/CIRCRESAHA.111.248401.