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Ralph Knöll group

Our research aims to combine the strengths of the ICMC Regenerative Cardiology Program to foster innovative science-based strategies, technologies, and therapeutic platforms towards unraveling the epigenetic mechanisms underlying the biology of human cardiac disease.

Specific Research Objectives

1. Analysis of epigenetics, including genomic DNA methylation patterns in health and disease, unravelling of the underlying molecular mechanisms as well implementation of therapeutic strategies to exploit therapeutic potential of these modifications (together with AZ/MedImmune and Moderna Therapeutics).

2. Based on previous results, use of human genetics and genetically altered models for the development of translational studies in patients with clinically/genetically distinct forms of cardiomyopathy/CHF as a unique patient study subset, including HF-PEF (heart failure with preserved ejection fraction; KI/AZ).

3. Continuation of work in the context of the Leducq transatlantic network of excellence in regards to the evaluation of mechano-sensitive types of cell death (apoptosis or “mechanoptosis”), which includes evaluation of therapeutic interventions to avoid cardiac myocyte cell death during biomechanical stress.

Funding

  1. KI/AZ Integrated Cardio Metabolic Center
  2. Leducq Transatlantic Network
  3. Swedish Heart & Lung Foundation

Members

Ralph Knöll: Professor, Group leader

Professor Ralph Knöll was recruited to AstraZeneca from Imperial College where he was Professor and Chair of Myocardial Genetics from 2009 to 2014. He was formerly Professor and head of the Working Group of Cardiovascular Molecular Genetics at the Georg August University, Göttingen, Germany from 2004 to 2009. He received his professional training as a Postgraduate Researcher and then Group Leader at the Institute of Molecular Medicine, UC San Diego, from 1999 to 2004 and clinical training at the University Hospital Benjamin Franklin, Free University Berlin (Charité) from 1996 to 1999. He received his doctoral degree at the Max-Planck-Institute of Physiological and Clinical Research, Department of Experimental Cardiology, and was educated at Johann Wolfgang Goethe University Medical School, Frankfurt and Justus Liebig University Medical School, Giessen.

He received several prestigious awards, including the Fritz Acker Award of the German Cardiac Society (2007), the Theodor Frerichs Award of the German Society for Internal Medicine (2003) and an Astra Zeneca Award in Basic Science (2002).

Professor Knöll is a Member of several Editorial Boards including Basic Research in Cardiology, as well as a referee for a number of other prominent journals, including Circulation, Circulation Research, Journal of Molecular and Cellular Cardiology, European Heart Journal, Molecular and Cellular Biochemistry, European Journal of Heart Failure, and Clinical Cardiology, among others. He is also a Member of the International Society for Heart Research (ISHR), British Society for Cardiovascular Research (BSCR), European Society of Cardiology (ESC – nucleus member and treasurer of the Working Group of Myocardial Function), the American Heart Association (AHA), British Pharmacological Society (BPS) and the German Cardiac Society (DGK), among others.

He is based at AstraZeneca in Mölndal as well as at the recently established Integrated Cardio Metabolic Center at the Karolinska Institue (ICMC/KI) and has a strong interest in genetics, physiology and pharmacology of the cardiovascular system. His research aims to combine the strengths of the ICMC Regenerative Cardiology Program to foster innovative science-based strategies, technologies, and therapeutic platforms towards unraveling the epigenetic mechanisms underlying the biology of human cardiac disease. The program will capitalize on the internal strengths of KI in the fields of regenerative/developmental/human stem cell biology in general, unique and well-curated patient registries and human tissue/cell resources.

His program will integrate the strengths of AstraZeneca in terms of drug development know-how, chemical screening, larger scale biology/bioinformatics/higher throughput capacity, regulatory and toxicology expertise, large animal model systems, and larger scale production. Also, he will take advantage of AZ/MedImmune (recombinant protein/peptide design and production, biological therapeutics know-how) and collaboration with Moderna Therapeutics (synthetic modified mRNA therapeutics for cardiovascular disease in general).

Zaher Elbeck, PhD student

I received my first master degree in Bioanalytical Chemistry in 2011, and my second master degree in 2014 in Molecular Life Science from Stockholm University and Karolinska Hospital with the focus on stem cell biology. I joined Prof. Knöll’s group in October 2014 and currently I am doing my PhD. My research project is focusing on understanding the epigenetics mechanisms that underlie heart failure in human patients with reduced ejection fraction and preserved ejection fraction.

Payam Haftbaradaran Esfahani, PhD student

I have completed my MSc in Bioengineering from Imperial College London where I have been a member of Prof. Knöll’s group, working on mechanical stimulation of Src kinase using magnetic twisting cytometry. In 2015 I have started my PhD in Prof. Knöll’s group at ICMC. My research focus is the effect of cell shape on gene expression and downstream signaling. In my study I am developing a computer-based mathematical model to simulate the effect of cardiomyocyte contraction on its down-stream signaling. Moreover, I use single-cell RNA sequencing data to decipher the effect of cardiac cell morphology on its pattern of gene expression.

Bakhtiar Hossain: Research Engineer, PhD

I have completed my PhD in Nutritional Biology from the University of California, Davis, USA, where I developed animal models to study the effect of supplementation during pregnancy. We observed that zinc supplementation of zinc-adequate mothers during pregnancy affects intestinal iron transporters in newborns. Since then I conducted studies to improve vitamin A and zinc status in developing countries. Recently, I assessed epigenetic alterations and oxidative stress influenced by environmental pollutants as a FAS Marie Curie Fellow at Lund University, and found that environmental cadmium and arsenic exposure affects epigenetic modification of cancer causing genes adversely.

I joined Ralph Knöll’s group in June 2017, and my research focus is to identify epigenetic mechanisms underlying heart failure, where I am analysing genome-wide data from next generation sequencing, including DNA methylation and hydroxymethylation, RNA-seq, and single cell RNA-seq from transgenic mice and affected humans.

Humam Siga: Research assistant

I had studied in the Biotechnology Engineering Department at the University of Aleppo, Syria for 4 years. Throughout my previous studies I gained a very good background in biology, chemistry, microbiology, bioinformatics and genetics, in both the theoretical and the practical sides.

I joined Prof. Knöll's group in January 2016 and I work as a research assistant by providing technical support with the group projects by performing several laboratory techniques such as: Genotyping, Western Blot, qPCR, in vivo work and Echocardiography.

Alumni

Nina Gennebäck: Postdoc, PhD (Feb 2015 – May 2016)

Ali Tabish: Postdoc, PhD (July 2015 – April 2016)

Sven Sagasser: Guest researcher, PhD (3 months)

Tim Stuedemann: Erasmus exchange student, Bachelor student from University of Göttingen, Germany (April – July 2016)

Aris Alexiadis: Erasmus exchange student, Undergraduate student from Exeter University, UK (Aug 2016 – July 2017)

Raquel Firnkes: Technical support (6 months)

Patricia Rodrigues: visiting PhD student, University of Porto, Portugal (May – Nov 2017)

Sakhtivel Sadayappan: Visiting Professor, PhD, University of Cincinnati, The United States (July – Sep 2015)

Valerio Azzimato: Postdoc, January 2015 – January 2018

Byambajav Buyandelger, Assistant Professor, PhD, August 2008 - June 2018

Selected publications

Viswanathan SK, Puckelwartz MJ, Mehta A, Ramachandra CJA, Jagadeesan A, Fritsche-Danielson R, Bhat RV, Wong P, Kandoi S, Kuffel G, Pesce LL, Zilliox MJ, Durai NB, Verma RS, Molokie RE, Suresh DP, Khoury PR, Thomas A, Sanagala T, Tang HC, Becker RC, Knöll R, Shim W, McNally EM, Sadayappan S. Cosegregation of the novel mybpc3 d398v variant and mybpc3δ25bp promotes cardiomyopathy. Journal of the American Medical Association (JAMA),2018;3(6):481-488

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