Telomere shortening in heart failure – the role of inflammation reactive oxygen species, DNA-repair and telomeric repeat-containing RNA (TERRA)

1 PhD project offered in the IPP summer call 2021

This project is part of the Science of Healthy Ageing Research Programme (SHARP).

Scientific background

Heart failure (HF) has a prevalence of 1-2% of the adult population and more than 10% of people over 70 years of age in developed countries, thereby rendering it among the most common causes of death, and hence imposing a significant burden of morbidity, mortality and healthcare costs on society. Cumulating evidence suggests a significant role of telomere length dynamics and altered telomere signaling in the pathogenesis of HF, although the exact mechanisms remain unknown.

Reactive oxygen species (ROS) have been identified as a major factor driving cardiovascular disease. More specifically, ROS contribute to the deterioration of cardiac function in HF of diverse etiologies. On the other hand, oxidative DNA-damage has long been suspected to drive telomere shortening, because the tightly folded, guanine-rich and shelterin-loaded telomeric structure appears especially sensitive to oxidative damage and at the same time, inaccessible to the common DNA-repair machinery.

Long non-coding transcripts of subtelomeric and telomeric sequences (telomere repeat-containing RNA “TERRA”) orchestrate telomere maintenance, but can also lead to telomere loss if not properly regulated. Remarkably, during myocardial stress, several phenomena occur in cardiomyocytes that are prerequisites for TERRA-expression. In the project we will investigate the contribution of TERRA in telomere maintenance/loss in the development of HF.

Cumulating data support the concept of a senescence associated secretory phenotype (SASP) - the secretion of mediators by senescent cells resulting in chronic inflammation regulating tumor suppression and wound healing/tissue regeneration. TERRA proved to be among the most abundant transcripts in extracellular (exosome) fractions derived from both normal and cancer patient blood plasma and these TERRA-containing exosomes induced a strong inflammatory response. The spatial and temporal orchestration of immune cells and inflammatory mediators play a central role in lesion size and recovery after myocardial injuries of diverse etiologies including myocardial infarction and myocarditis. We will therefore investigate the influence of extracellular/secreted TERRA on myocardial inflammation and the subsequent effects on the development of HF.

PhD project: The role of TERRA in ROS-induced telomere shortening in heart failure – telomere homeostasis and senescence associated secretory phenotype     

We will investigate the role of TERRA in the telomere homeostasis, specifically in ROS-induced telomere attrition, in the myocardium in the pathogenesis of heart failure in cellular and murine models of heart failure.

Further we will explore if and how extracellular (exosomal) TERRA contributes to the development of HF after myocardial infarction and upon excess neurohormonal activation, via modulation of a myocardial inflammatory response in cellular and murine models of heart failure.

We are looking for a student with a strong interest in cardiovascular biology and the biology of ageing. In this translational project we will bring together and intertwine the expertise for TERRA-biology (Brian Luke / IMB) and the expertise for heart failure in cells, animal models and patient care (Philip Wenzel, Moritz Brandt / Cardiology, University Medical Center). We are looking for a motivated and curious student with experience in cell culture and (small) animal work who is eager to explore the role of TERRA in heart failure from bench to beside.

If you are interested in this project, please select Moritz Brandt as your group preference in the IPP application platform.

Publications relevant to the project

Lockhart A, Pires VB, Bento F, Kellner V, Luke-Glaser S and Luke B (2019) RNase H1 and RNase H2 are differentially regulated to process RNA-DNA hybrids. Cell Reports, 29:2890-2900.e5 Link

Graf M*, Bonetti D*, Lockhart A*, Serhal K, Kellner V, Maicher A, Jolivet P, Teixeira MT and Luke B (2017) Telomere length determines TERRA and R-loop regulation through the cell cycleCell, 170:72–85 (*indicates joint contribution) Link

Brandt M, Garlapati V, Oelze M, Sotiriou E, Knorr M, Kroller-Schon S, Kossmann S, Schonfelder T, Morawietz H, Schulz E, Schultheiss HP, Daiber A, Munzel T,  Wenzel P (2016) NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathySci Rep, 6:32554 Link

Tan J, Duan M, Yadav T, Phoon L, Wang X, Zhang JM, Zou L, Lan L (2020) An R-loop-initiated CSB-RAD52-POLD3 pathway suppresses ROS-induced telomeric DNA breaks. Nucleic Acids Res, 48(3):1285-1300 Link

Wang Z, Deng Z, Dahmane N, Tsai K, Wang P, Williams DR, Kossenkov AV, Showe LC, Zhang R, Huang Q, Conejo-Garcia JR, Lieberman PM (2015) Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes. Proc Natl Acad Sci U S A, 2015. 112(46):E6293-300 Link

 

Contact

Dr Moritz Brandt (If you are interested in this project, please select Moritz Brandt as your group preference in the IPP application platform.)

Email

Webpage

Prof. Philip Wenzel

Email

Webpage

Prof. Brian Luke

Email

Webpage