Epigenetic landscapes pave the way for drug development and intervention in inflammatory heart failure

Bakgrund:

Cardiovascular diseases (CVDs) are the primary cause of morbidity and mortality globally and share an inflammatory pathogenesis. Heart failure (HF), can be associated with reduced or preserved left ventricular ejection fraction (LVEF), termed HFREF and HFPEF, respectively. While HFREF has been well known for many decades, HFPEF was described only a few years ago accounting for 50% of all HF cases with a clear inflammatory pathogenesis, similar to neuroinflammatory diseases. Currently, no accepted therapy is available for HFPEF which contributes to the poor prognosis.

Målsättning:

Here we will exploit the genetic/epigenetic/transcriptomic axis, identify drug targets and we will develop novel therapeutic strategies to treat HF. This strategy already proved successful by our development of drugs targeting pro-survival pathways. Arbetsplan:

Here we implement an integrative, multidisciplinary platform with the aim to provide mechanistic insights into the pathophysiology of HF by defining the differential epigenetic landscape in human samples, employing whole-genome 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) analysis at single base resolution, in combination with single-cell and bulk RNA sequencing and open chromatin analysis, proteomics and bioinformatics.

Based on our preliminary data, where we can rescue various genetic HFrEF and HFpEF models with novel, recently developed, anti-inflammatory and anti-oxidative compounds or therapeutic interventions using novel modalities, including antisense oligos targeting calcium metabolism and innovative approaches whereby we directly target the sarcomere, we can significantly improve myocardial performance.

Betydelse:

The purpose of this project is to (re)define information flow via the genetic-epigenetic and transcriptomic axis in understanding the pathophysiology of HF omics to develop novel therapies. This project will significantly pave the way for intervention by improving our current knowledge with regard to the epigenome of the HF axis. Thus, by introducing novel paradigms to explain disease and facilitate the identification of unique and innovative therapeutic strategies, major contributions can be made to the identification of innovative therapeutic strategies targeting HFREF and HFPEF and to modern molecular medicine in general.