Page 1 of every genetics textbook states that the molecular machinery inside cells transforms the information from DNA into functioning proteins. Reality is, however, not nearly that simple, because numerous auxiliary proteins help to fold and modify the proteins before they are ready to function. In addition, dysfunctional proteins cause many diseases that are not yet under control.
Understanding how the formation of proteins influences the development of diseases requires that researchers buckle down and determine what is happening. This is exactly what Kresten Lindorff-Larsen from the Department of Biology of the University of Copenhagen does. The Novo Nordisk Foundation has just awarded him a grant of DKK 60 million to determine how researchers can understand and ultimately predict how changes in our DNA and proteins can end up making us sick.
“We focus specifically on the roles that loss of protein stability, misfolding of proteins and protein degradation play in disease. Understanding these phenomena will both enlighten unknown processes in cells and hopefully improve methods for diagnosis, and also lead to new strategies for developing treatments,” says Kresten Lindorff-Larsen.
This potentially revolutionary research project is just one of the six major research projects that are now receiving DKK 60 million each from the Foundation through its Challenge Programme. The Foundation established the Challenge Programme to support and promote world-class research aimed at finding solutions to challenges in global technology or health.
Read more about the five other grant recipients below.
The Foundation awards grants of up to DKK 360 million each year through the Challenge Programme, which has different themes each year This year’s six grants are given within three themes:
- Protein Chemistry – Structure, Function and Application;
- Pathophysiology, Diagnosis and Treatment of Nonalcoholic Steatohepatitis; and
- Understanding Obesity at the Cellular Level.
Three grants within protein chemistry research
Protein chemistry is a new grant area for the Foundation. In addition to Kresten Lindorff-Larsen’s research project, two other projects within this theme received grants of DKK 60 million for 6 years of research.
The second grant recipient is Torben Heick Jensen, Professor, Department of Molecular Biology and Genetics, Aarhus University. His research project aims to understand what the body’s cells do with the genetic waste that remains when genes are translated into proteins.
“Our genetic material, the genome, produces RNA that forms either proteins or independent RNA molecules. However, genomic DNA is hyperactive, and only a fraction of the RNA produced ends up being functional molecules. The rest degrade. Which molecular machines detect and remove inappropriate RNA so that the cells do not drown in their own molecular waste? This is the question that the Exo-Adapt research centre will focus on for the next 6 years,” explains Torben Heick Jensen.
Researchers aim to revolutionize protein chemistry
The Foundation has awarded the last grant within protein chemistry for research on intrinsically disordered proteins.
These proteins, which have no three-dimensional structure, have been an enigma to researchers globally. Throughout the history of protein chemistry, the dogma has been that proteins definitely need a three-dimensional structure to fulfil their function. But intrinsically disordered proteins do not have this.
These structureless proteins are fully functional but seem to change form at random, and researchers do not yet know how and why they are able to communicate.
This will hopefully end now, because based on a Foundation grant, Birthe Brandt Kragelund, Professor, Department of Biology, University of Copenhagen will examine this biomolecular quandary. The purpose of the project is to improve understanding of the intrinsically disordered proteins and the role of the disorder and specificity in protein chemistry in the laboratory and in nature.
“The project gathers internationally leading experts on intrinsically disordered proteins across a wide range of fields. They have the complementary expertise, scientific experience, flexibility and impact to create a conceptual basis for transforming protein chemistry and all related disciplines, including the health and medical sciences,” says Birthe Brandt Kragelund.
Researchers aim to advance development of new therapies for NASH
Professor Sakari Kauppinen from the Center for RNA Medicine, Aalborg University receives DKK 60 million to establish an international research consortium (NASH-RC) to advance development of new therapies for treatment of nonalcoholic steatohepatitis (NASH).
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide with a global prevalence of approx. 25%. NASH is a progressive subtype of NAFLD characterized by the presence of ballooned hepatocytes, inflammation and fibrosis. NASH is strongly associated with obesity and the metabolic syndrome and is rapidly becoming the leading cause of end-stage liver disease, liver transplantation and hepatocellular carcinoma, underscoring the need for new therapies for treatment of NASH.
The NASH-RC project focuses on developing microRNA-targeted therapeutics as a new treatment paradigm for NASH.
“Our goal is to discover drugs for effective and safe inhibition of metabolic microRNAs and assess their therapeutic potential to treat NASH in highly relevant preclinical models of NASH. Furthermore, we will evaluate hepatic and circulating microRNAs in human samples as biomarkers for NASH. We believe that successful development of combined diagnostics and microRNA-targeted therapeutics has the potential to guide new treatment options for patients with NASH,” says Sakari Kauppinen.
Taking obesity research to the cellular level
The Foundation has awarded the last two Challenge Programme grants for this year for research on understanding obesity at the cellular level.
Susanne Mandrup is a Professor at the Department of Biochemistry and Molecular Biology of the University of Southern Denmark. Her research project aims to understand the signalling function of fat cells (adipocytes) and how this changes as obesity develops.
“We will use experimental and computer-based techniques to obtain a whole new understanding based on systems biology of how fat cells receive and respond to cellular signals. The goal is to understand how this signalling function varies with sex, genetic factors and the specific fat deposits and how changes in these signalling functions as obesity develops contribute to the pathophysiological effects of obesity,” explains Susanne Mandrup.
The second grant recipient within this theme is Romain Barrès, a Professor from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen. Together with his colleagues, he will spend the next 6 years delving into and understanding how the diet of our ancestors has affected the weight and health of subsequent generations at the cellular level through epigenetic changes.
“The grant will enable us to establish a scientific community with the potential to build bridges between several disciplines and expertise in epigenetics, physiology, chromatin structure, metabolism, comparative biology and bioinformatics. We hope to develop innovative strategies to improve the metabolic health of the coming generations by making recommendations related to lifestyle,” says Romain Barrès.
All six projects are being carried out in collaboration with several partners in Denmark and other countries.
About the individual projects
Theme: Protein Chemistry – Structure, Function and Application
Kresten Lindorff-Larsen, Professor, Department of Biology, University of Copenhagen, Denmark
PRISM: Protein Interactions and Stability in Medicine and Genomics
Torben Hansen, Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
Michele Vendruscolo, Professor, Department of Chemistry, University of Cambridge, United Kingdom
Douglas M. Fowler, Associate Professor, Department of Genome Sciences, University of Washington, Seattle, USA
The researchers will integrate computer-based biophysics, high-throughput protein chemistry and genome analysis to understand how changes in the genome affect protein biology and how this knowledge can be used to diagnose and ultimately treat people with diseases.
Torben Heick Jensen, Professor, Department of Molecular Biology and Genetics, Aarhus University, Denmark
Function, Structure, Regulation and Targeting of Exosome Adapter Complexes
Elena Conti, Honorary Professor, Ludwig Maximilian University of Munich and Director, Max Planck Institute of Biochemistry, Martinsried, Germany
Jens S. Andersen, Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense
The purpose is to understand the degradation of RNA by examining the structural and functional relationships between RNA exosomes and exosome adapters.
Birthe Brandt Kragelund, Professor, Department of Biology, University of Copenhagen, Denmark
REPIN – Rethinking Protein Interactions
Benjamin Schuler, Professor, Department of Biochemistry, University of Zurich, Switzerland
Rasmus Hartmann-Petersen, Professor, Department of Biology, University of Copenhagen, Denmark
Karen Skriver, Professor, Department of Biology, University of Copenhagen, Denmark
The researchers will investigate how the lack of structure in proteins influences protein interactions through a series of experiments ranging from studies of individual molecules to investigating whole organisms.
Theme: Pathophysiology, Diagnosis and Treatment of Nonalcoholic Steatohepatitis
Sakari Kauppinen, Professor, Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Denmark
Therapeutic Targeting of Metabolic MicroRNAs as a New Treatment Paradigm for NASH
Anders Näär, Professor, Department of Nutritional Sciences & Toxicology, University of California, Berkeley, USA
Pier Paolo Pandolfi, Professor, the Cancer Center and Institute for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Ryan Temel, Associate Professor, Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, USA
The NASH-RC project aims to develop new, microRNA-targeted therapeutics for treatment of nonalcoholic steatohepatitis.
Theme: Understanding Obesity at the Cellular Level
Susanne Mandrup, Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense
ADIPOSIGN – Center for Adipocyte Signaling
Jan-Wilhelm Kornfeld, Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense
Madan Babu, Research Director, Regulatory Genomics and Systems Biology Group, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
Zachary Gerhart-Hines, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
The researchers will use today’s most advanced technologies to obtain in-depth understanding of the signalling pathways of fat cells and how they depend on genetic factors, sex and the level of obesity.
Romain Barrès, Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
Ancestral Causes of Obesity: Understanding Epigenetic Transmission by Spermatozoa
Stephen Simpson, Academic Director, Charles Perkins Centre, University of Sydney, Australia
Marcelo Nobrega, Professor, Department of Human Genetics, University of Chicago, IL, USA
The researchers will shed new light on how obesity- or diet-induced epigenetic changes in sperm influence the development of metabolic dysfunction among children.
Christian Mostrup Scheel, Senior Press Officer, phone: +45 3067 4805, [email protected]