13 SUND-forskere henter 130 millioner kroner til spændende projekter

NNF Hallas-Møller Ascending investigator

Associate Professor Jesper B. Andersen, BRIC - 9.999.492 kr.
Titel: Viral exposures dictate the inflammatory microenvironment in liver cancers

"In Europe, the bile duct cancer incidence has increased 236% since 1980, with regional difference rising 7-fold over the past decade. Whereas cancer mortality has declined and therapy in other cancers improved, surgical resection still remains the only curative option for this patient group. The disease is often sporadic with unknown etiology, and patients are diagnosed at late-stage with locally advanced or metastatic disease, and a 5-year prognosis below 10%. In my research program, I will determine the viral exposures in a patient’s life and use these unique molecular footprints as guides to define the trigger of chronic inflammation and cancer. B cells are our humoral guardians responding to infections by producing antibodies. Yet, their pathobiological role and molecular states in contact with tumor cells are unknown. Thus, determining novel B cell tumor evasion mechanisms in bile duct cancer will allow us to start to develop specific B cell targets."

Associate Professor Katrine Schjoldager, ICMM - 9.999.551 kroner
Titel: Exploring the Functional Consequence of Bioactive Peptide Glycosylation

"Bioactive peptides (neuropeptides and peptide hormones) are key regulators of numerous physiological processes from blood glucose levels to blood pressure, mood and perception of pain. Dysfunctional bioactive peptide (BP) signalling is associated with a number of diseases including diabetes, Alzheimers and hypertension, and BPs constitute a major class of promising druggable compounds. Understanding how peptide signalling is modulated in health and disease is therefore of great importance. My team has discovered that a large number of bioactive peptides are modified with sugar-moieties, and we want to establish new and improved methods and a deeper understanding of how these sugar-modifications effect or regulate the functions of the bioactive peptides. The project has significant promise for discovery of novel designs for peptide therapeutics for a range of common diseases."

Associate Professor Andrew Williams, IVH - 9.997.950 kroner
Titel: Understanding how gut metabolites regulate type-2 mucosal immunity

"There is increasing evidence that diet and the gut microbiota may interact to regulate the immune system, and how the body responds to infection. Disturbances in this complex relationship may result in chronic infections or autoimmune diseases.Dietary fibre promotes a healthy gut microbiota and may reduce chronic inflammation. However, we have discovered that in some contexts high levels of fibre may increase susceptibility to infection with intestinal parasites. Given that parasitic worms infect more than a billion people worldwide and represent a major public health concern, there is a pressing need to understand this interaction. Here, we will use mice and pigs to model the infectious process to investigate how dietary fibre changes the gut microbiota and alters the immune response."

Associate Professor Julien Duxin, CPR - 9.440.226 kroner
Titel: Mechanisms of sensing, removal, and bypass of DNA-protein crosslinks

"DNA-protein crosslinks (DPCs) are dangerous lesions found in our genome. If not repaired, DPCs cause aging and cancer in humans. Moreover, most chemotherapeutics used in the clinic kill cancer cells by generating DPCs. Despite their relevance to humans, we know little about how these lesions are repaired. A major difficulty is to reliably monitor DPCs in cells, which is currently not possible using existing methods. To bypass this barrier, we have recently used protein extracts derived from frog eggs to recapitulate DPC repair in a test tube. This unique approach allowed us to uncover the existence of specialized processes operating in our cells that remove DPCs and thereby prevents cancer and aging. Because these lesions are incredibly diverse, we are now proposing to use our unique approach to study the repair of the major classes of DPCs so that we can establish overarching principles of how these lesions are sensed and removed from the genome."

NNF Hallas-Møller Emerging Investigator

Associate Professor Thomas Miller, ICMM - 9.995.219 kroner
Titel: Defining the molecular mechanisms of replication-coupled DPC repair using EM-based visual biochemistry (DPC-Rep-EM)

"Each time our cells divide they must accurately duplicate their DNA so that both daughter cells receive an identical set of genetic instructions. A failure to accurately duplicate the genome can lead to genome instability and cause age-related disorders, including cancer. Genomes of all organisms are duplicated by protein machines called replisomes, which frequently encounter ‘obstacles’ that can prevent faithful DNA replication. This project will reveal how replisomes normally overcome these obstacles in healthy cells and why a failure in these processes causes human disease. To do this, we will use electron microscopy to image replisomes as they encounter and coordinate the repair of DNA-protein crosslinks (DPCs), a common and highly toxic obstacle to DNA replication. Our results will provide insights into how our cells maintain genome stability and may identify opportunities for enhancing current chemotherapies that kill cancer cells by forming DPCs on DNA.”

Associate Professor Rebecca Louise Miller, ICMM - 10.000.000 kroner
Titel: Deciphering the sulfation code of polysaccharides – a molecular code orchestrating myriads of essential biological interactions

"Heparin is a widely used anti-clotting drug. Although most biologic drugs are produced using recombinant technologies, heparin persists as a product purified from animal tissues. A cell-based system for production of heparin would eliminate risk of supply shortage and contamination, which have had serious outcomes, as well as bypass the use of animals and lengthy purification processes. Production of recombinant heparin in mammalian cells requires engineering the heparan sulfate biosynthetic pathway, which consists of over 20 biosynthetic enzymes. My project aims use genetic methods and advance technologies to engineer and install heparin biosynthesis in a cell line. We have reached a stage in this endeavour to predict that we can design and produce improved heparin without the most serious side-effects. The project thus holds promise for sustainable, better, and safer heparins."

Assistant Professor Kathleen Stewart-Morgan, ICMM - 10.000.000 kroner
Titel: Origin and Functions of Epigenetic Heterogeneity in Germ Cell Selection

“Primordial germ cells, the precursors to sperm in males and oocytes in females, undergo many changes and transformations throughout development. One of the most dramatic changes is to the epigenome, the proteins and chemical tags on DNA that regulate how the cell “reads” its genome. Germ cell development also entails waves of proliferation, where germ cells divide and multiply, and apoptosis, where a proportion of germ cells die. What differentiates germ cells that survive apoptosis from those that die is unclear. By assaying the germ cell epigenome throughout development and relating epigenome changes to proliferation and apoptosis, this project will examine the role of epigenome reprogramming in germ cell survival. This will provide new insights into how epigenome reprogramming in germ cells occurs, and the epigenome’s role in germ cell quality and function.”

NNF Ascending Investigator Grant - Endocrinology and Metabolism

Associate Professor Tuomas Kilpeläinen, CBMR - 10.000.000 kroner
Titel: In Adipose Tissue: Identifying Genetic Mechanisms that Uncouple Obesity from Insulin Resistance

“Obesity often leads to insulin resistance and an increased risk of type 2 diabetes. However, not all individuals with obesity are similarly affected. Given the same weight gain, individuals may be either protected from or predisposed to metabolic dysfunction. This variability has been attributed to individual differences in the characteristics of the excess adipose tissue. However, there remains a lack of understanding of the specific adipose tissue properties that underlie differential responses to weight gain and obesity. The aim of the present project is to understand the adipose tissue mechanisms that either protect from or predispose to insulin resistance and type 2 diabetes. The project builds on human genetic findings made in large populations and applies a range of approaches to connect the genetic variants to adipose tissue biology. The new understanding emerging from the project may point towards more effective ways to treat insulin resistance and type 2 diabetes.”

Associate Professor Christoffer Clemmensen, CBMR - 10.000.000 kroner
Titel: Glutamatergic NMDA receptor signaling in energy homeostasis: Implications for obesity treatment

“The increasing prevalence of obesity represents a growing threat to public health. Challengingly, obesity is a rather treatment-resistant condition and many patients do not obtain the benefits of pharmacological or lifestyle-based interventions. Notably, human genetic studies point to an important role for glutamatergic neurotransmission and neurostructural changes in body weight regulation and obesity pathogenesis. However, this biology is incompletely understood and has yet to undergo pharmacological scrutiny for obesity treatment. In this project proposal the overarching aim is to dissect the importance of the glutamatergic NDMA receptor and its related signaling complex, in physiological and pharmacological regulation of body weight homeostasis. This research holds promise to illuminate a hitherto unknown signaling pathway essential for the regulation of energy homeostasis and to evaluate its druggability for obesity treatment.”

NNF Distinguished Investigator

Professor Chuna Ram Choudhary, CPR - 9.999.872 kroner
Titel: Elucidating the mechanisms of mammalian dynamic gene regulation

“The human body contains hundreds of different types of cells that perform different biological functions. Remarkably, all cells contain an identical copy of the genome, yet the same genetic information is differentially decoded in different cells, allowing activation of a different set of genes in different cells. Different gene products are then translated into different proteins that perform different functions, and ultimately give rise to functionally different cell types. Regulatory genome elements, called enhancers, act as central regulators of gene transcription and enable cell-type-specific differential decoding of the same genome. How enhancers control some genes, without affecting others, remains a major unresolved mystery in biology. This project aims to provide a deeper mechanistic understanding of gene expression regulation in mammalian cells and illuminate the molecular principles by which enhancers activate their target genes.”

Professor Eva Hoffmann, ICMM - 9.988.699 kroner
Titel: Human genetic variation: molecular mechanisms and functional constraints

“Up to one in 20 children are born with congenital disorders that originated in the parents' sperm or egg. This is much higher than in other organisms and we have long wanted to understand what happens when parents pass on their DNA to their children. Questions such as what makes us different from our parents, how does our DNA change, and what can go wrong. We are now in a position to start addressing these fundamental questions about human genetics. We will generate an atlas of sequences from human eggs, sperm and embryos from earliest stages of development to explore what genetic changes we see and how these processes occur. Some of the processes lead to severe genetic aberrations that result in infertility and pregnancy loss, whereas others sustain development - understanding these features of human genetic variation may provide insight into congenital disorders and their origins.”

Clinical Professor Henning Bundgaard, IKM - 9.935.018 kroner
Titel: Impact of maternal risk factors and cardiac abnormalities in the offspring. Copenhagen Baby Heart Study – Impact (CBHS-I)

"Certain environmental factors and disorders in the expecting mother are associated with heart defects in the newborn. However, these factors may also be associated with more subtle abnormalities in the newborn heart that may present much later in life. This project will investigate the association between common maternal risk factors (diabetes, thyroid and connective tissue disorders) and more overt modifiable factors (smoking, weight and night-shifts) during pregnancy and the impact on the heart in the newborn and later in childhood, through heart examinations of children at birth and again at 5 and 10 years of age. This project will generate knowledge of which neonatally identified subtle abnormalities may require follow-up or even early intervention. The major expectation is to obtain insight into the effects or contributing factors to subgroups of cardiac disorders seen in adults including coronary artery disease, arrhythmias, heart failure, valve calcification and hypertension.”

Clinical Professor Kjeld Schmiegelow, IKM - 9.977.475 kroner
Titel: PREDICT: Predispositions Revisited – Exploring Diagnostics, Interventions for Cure & Toxicity (childhood cancer as a Rare Disease prototype)

“We know of more than 6,000, most often hereditary, "rare diseases" (RD), including childhood cancer. Together, the RD affects more than 250 million people worldwide. In children, cancer is responsible for 20% of all deaths. In PREDICT, we will use cancer in children, and especially leukemia (most common childhood cancer), as a prototype for RD and provide new knowledge about what variations in human genetic material mean for the development of cancer (and other diseases) and for the course of the disease. Using modern genetic engineering, including a new method of analysis that we have developed, we will (i) identify individuals who have a congenital increased risk of developing cancer, (ii) identify whether the new method of analysis can be used in the national screening of newborns for hereditary diseases, (iii) examine thousands of cancer patients to map the effects of hereditary factors on cure rates and the incidence of side effects, and (iv) uncover how patients and healthy individuals experience the application of the new knowledge about their genes.”