Grants

A large proportion of patients with schizophrenia spectrum disorders suffer from paranoid ideas, that inflict on their daily functioning and quality of life, and are not alleviated by current pharmacological and psychotherapeutic treatments. Hence, there is a need to develop new, effective treatments. The current randomised, controlled trial "Face your Fears" investigates the effectiveness of virtual reality exposure in alleviating paranoid ideas and consequently improving daily functioning (e.g. vocational functioning, social functioning) and quality of life for patients with a schizophrenia spectrum disorder. The trial enrolls 256 patients with a schizophrenia spectrum disorder, that are randomised to either Cognitive behavioral Therapy (CBT) or CBT + VR exposure. Assessments are conducted at baseline, at cessation of treatment (3-months), and at 6-months follow-up. Primary outcome is level of paranoid ideas measured with Green Paranoid Thought Scale ideas at 3-months follow-up.

This project will test the innovative hypothesis that pancreatic ductal adenocarcinoma (PDAC) progression is caused by the interplay between acidic microenvironment and DNA Damage Response (DDR) pathway mutations. PDAC survival rate is less than 8% and it is predicted to become the leading cause of cancer mortality by 2030. Molecular mechanisms underlying the disease are not fully understood, hampering development of new treatments that are urgently needed. We will employ murine 3D organoid models of early PDAC. We will introduce relevant DDR pathway mutations and expose organoids to acidic pH simulating conditions during PDAC development. Next, we will analyze gene expression, assess their response to drugs used in cancer clinical management and tumour growth and metastasis in syngeneic mouse model. We expect that results generated in this project will significantly impact pancreatic cancer research and may point to promising early-stage PDAC biomarkers and drug target candidates.

This project is focused on chromatin factors regulating the methylation of Lysine 4 on Histone H3 (H3K4). Genes encoding for H3K4 regulating factors are essential for normal development, and their mutations are known to be causally involved in cancer and neurodevelopmental disorders. H3K4 methylation is commonly depicted as required for transcriptional activation. However, recent publications are not consistent with this description, leaving the actual impact of H3K4 methylation an outstanding open question. The overall aim of this project is to delineate how H3K4 methylation, per se, affects transcription and to identify the biological consequences of H3K4 methylation loss in a whole organism. To this end, we will use C. elegans as a model system, taking advantage of the evolutionary conservation of the H3K4 regulating complexes and the relative ease by which this model can be used to study the biological impact of mutations.

Malaria is an infectious disease caused by parasites invading erythrocytes. Individuals with sickle-cell trait (HbAS), an inherited blood disorder, are protected from severe disease, but not from infection. The protection appears associated with altered expression of a protein family called PfEMP1 on the surface of infected erythrocytes (IEs). This appears to reduce the adhesion of IEs to vascular endothelium that causes organ-specific inflammation and life-threatening complications. Although the epidemiological association between HbAS and protection against severe malaria is well documented, it is not understood in molecular detail how HbAS protects aginst severe clinical outcome. Here, we propose to use advanced tools to assess a set of specific, novel, plausible, and testable hypotheses about how HbAS confers protection against severe malaria. The proposed research is likely to yield important new insights about the interplay between these deadly parasites and the immune system.

The planned studies aim at understanding P4-ATPases, also known as flippases. They “flip” specific phospholipids between leaflets of cellular membrane lipid bilayers, powered by ATP. Flippases belong to the P-type ATPase protein family, which is well known for Ca-ATPase and Na,K-ATPase. Flippases are less well understood, although they account for as much as 40% of the P-type ATPase genome, and severe pathological conditions result from genetic defects of flippases. We address the flipping mechanism and electrogenicity of the flippase ATP8A2. Highly purified preparations of ATP8A2 mutants and wild type suitable for functional and structural studies are produced from protein expressed in cell culture. Based on recently obtained information on the structure of ATP8A2 we design mutagenesis experiments to trace the lipid transport pathway in the protein and the reaction step resulting in electric current, and we examine whether the flippase interacts electrically with the Ca-ATPase.

Acute heart failure is a potentially life-threatening condition, reaching mortality rates of up to 50% in patients with cardiogenic shock, despite advanced intensive care and mechanic circulatory support. Our group has shown that infusion of ketone bodies increases cardiac output by 40% in stabile patients with chronic heart failure. However, the effects of ketone bodies in patients with acute heart failure or cardiogenic shock remains to be studied. In four randomized, placebo-controlled crossover trials we will investigate the effects of two different ketone supplements (ketone salts and ketone esters) in patients with varying degrees of heart failure including patients with cardiogenic shock, at the intensive care unit. The present study will determine the potential beneficial effects of ketone supplements in patients with acute heart failure and cardiogenic shock.

Turner syndrome (TS) is a rare sex chromosome aneuploidy. The lack of one X chromosome is associated with a number of health problems involving multiple organs. However, the morbidity pattern seen is heterogeneous with within karyotype variation. The genetic background explaining the clinical phenotype is not understood. The goal of this project is to clarify the etiology and pathogenesis of TS by uncovering the genomic, epigenomic and transcriptomic basis for the TS phenotypes. All studies on the genomics of Turner syndrome have so far been unsupervised, but have generated a list of candidate genes. This proposal consists of two work packages: 1. A epigenomic and transcriptomic study in TS of multiple tissues with a temporal component aimed at elucidating tissue-specific and temporal changes and finding new phenotypic candidate genes. 2. Based on previous studies we will functionally evaluate TS candidate genes in a Zebrafish in vivo modelling system.

Acute kidney injury (AKI) is a common and serious clinical syndrome defined by an abrupt decrease in kidney function caused by a range of acute conditions. Due to an increasing incidence and associated high morbidity and mortality, AKI is now considered a global health problem. There is a need for knowledge about the impact of AKI and initial renal recovery on long-term prognosis in the general population. Through a series of population-based studies, the proposed project will develop a model to examine the long-term prognosis of AKI with and without initial renal recovery. Utilizing Danish health registries, we will create an internationally unique cohort with comprehensive high-quality data on both preexisting kidney function and confounders, and with complete follow-up for chronic kidney disease, cardiovascular disease, and death. This will be important to understand the impact of AKI, to help guide development of future treatments, and to plan follow-up of patients with AKI.

We will in this project integrate and unify the theories, algorithmic methods, and efficient implementations of two existing computational frameworks: MØD, which is based on graph transformation formalisms, and Kappa, which builds on concurrency theory. Both frameworks aim at analyzing large and complex chemical and biological reaction networks. They share their rigorous foundation on category theory, while having different strengths: MØD has a chemically quite explicit modeling level (representing molecules as undirected graphs), which e.g. allows for tracing individual atoms across many reactions. Kappa is aimed at studying causality in networks, which allows the concept of reaction pathways to be rigorously defined and studied. Combining these abilities will allow for foundational studies of, and computational solutions to, many questions in systems chemistry and biology, two areas in dire need of better computational methodologies due to the complexity of the involved networks.

Splice Switching Oligonucleotides (SSO) can bind to regulatory elements (REs) in RNA and regulate splicing if the important REs are known. Design of SSOs is, however, considered to be very cumbersome because identification of the REs to be targeted is not trivial. We have discovered that a general RE is present immediately downstream of a large number of SSO responsive exons. We coined it the Sweet Spot. We will investigate if Sweet Spots are as general as we suspect by massive parallel screening with SSOs targeting the Sweet Spot in 400 endogenous exons in their natural genomic context. The underlying regulatory mechanism will be thoroughly investigated experimentally (minigenes, SPRi etc.) and by bioinformatics. Finally, we will develop a machine-learning program to evaluate if an exon is responsive to Sweet Spot SSOs. Data from massive parallel testing will be used for training and data from functional characterization (minigenes, SPRi etc.) will be used for validation.