ERC FUNDED PROJECTS

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity. AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets. We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays. New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging

1 500 000 €

Start date: 2013-06-01, End date: 2018-05-31

There is a large need for revitalization of the research on coronary heart disease (CHD) including: a) improved risk prediction and more adequate individually-tailored treatment; and b) new targets for drug development based on pathways previously unknown to be involved in CHD pathophysiology. The overall goal of this proposal is to improve prevention and treatment of CHD through better understanding of the biology underlying disease development, identification of new biomarkers for improved risk prediction, and discovery of novel targets for drug development. The specific aims are to: 1) Establish and characterize causal genes in known CHD loci (gene regions) through: a) resequencing of known CHD loci; b) expression profiling in liver, arteries, myocardium and skeletal muscle; c) high-throughput protein profiling; and d) experimental follow-up in zebrafish (Danio rerio) models. 2) Discover new proteins, metabolites and pathways involved in CHD pathophysiology using global proteomic and metabolomic profiling to provide new biomarkers and drug targets. We will integrate genomic, transcriptomic, metabolomic and proteomic data from five longitudinal, population-based cohort studies with detailed phenotyping and one study with tissue collections for expression studies. The cohort studies include 36,907 individuals; there are 3,093 prevalent CHD cases at baseline and the estimated number of incident (new) events in previously healthy by 2016 is 2,202. In addition, we work with zebrafish model systems to establish causal CHD genes and characterize their mechanisms of action. We have access to unique study materials, state-of-the art methods, and a strong track record of successful projects in this field. To our knowledge, there are no other groups combining -omics methods to elucidate the whole chain from DNA variation to overt CHD in such large and well-characterized study samples. Further, we are unaware of other groups using zebrafish models to screen for and characterize causal CHD genes. Our work is anticipated to lead to new important insights into the pathophysiology of CHD, identification of new biomarkers for improved risk prediction, and discovery of novel targets for drug development.

1 498 224 €

Start date: 2014-01-01, End date: 2018-12-31

"One of the crucial formation channels of compact object binaries, including sources of gravitational waves, critically depends on catastrophic binary interactions accompanied by the loss of mass, angular momentum, and energy (""common envelope"" evolution - CEE). Despite its importance, CEE is perhaps the least understood major phase of binary star evolution and progress in this area is urgently needed to interpret observations from the new facilities (gravitational wave detectors, time-domain surveys). Recently, the dynamical phase of the CEE has been associated with a class of transient brightenings exhibiting slow expansion velocities and copious formation of dust and molecules (red transients - RT). A number of RT features, especially the long timescale of mass loss, challenge the existing CEE paradigm. Motivated by RT, I will use a new variant of magnetohydrodynamics to comprehensively examine the 3D evolution of CEE from the moment when the mass loss commences to the remnant phase. I expect to resolve the long timescales observed in RT, characterize binary stability in 3D with detailed microphysics, illuminate the fundamental problem of how is orbital energy used to unbind the common envelope in a regime that was inaccessible before, and break new ground on the amplification of magnetic fields during CEE. I will establish RT as an entirely new probe of the CEE physics by comparing my detailed theoretical predictions of light curves from different viewing angles, spectra, line profiles, and polarimetric signatures with observations of RT. I will accomplish this by coupling multi-dimensional moving mesh hydrodynamics with radiation, dust formation, and chemical reactions. Finally, I will examine the physical processes in RT remnants on timescales of years to centuries after the outburst to connect RT with the proposed merger products and to identify them in time-domain surveys. "

1 243 219 €

Start date: 2019-01-01, End date: 2023-12-31

Despite technological advances, industry struggles to develop new pharmaceuticals and therefore novel strategies for drug discovery are urgently needed. G protein-coupled receptors (GPCRs) play important roles in numerous physiological processes and are important drug targets for neurological diseases. My research focuses on modelling of GPCR-ligand interactions at the atomic level, with the goal to increase knowledge of receptor function and develop new methods for drug discovery. Breakthroughs in GPCR structural biology and access to sensitive screening assays provide opportunities to utilize fragment-based lead discovery (FBLD), a powerful approach for drug design. The objective of the project is to create a computational platform for FBLD, with a vision to transform the early drug discovery process for GPCRs. As structural information for these targets is limited, predictive models of receptor-fragment complexes will be crucial for the successful use of FBLD. In this project, computational structure-based methods for discovery of fragment ligands and further optimization of these to potent leads will be developed. These techniques will be applied to address two difficult problems in drug discovery. The first of these is to design ligands of peptide-binding GPCRs that have been challenging for existing methods. One of the promises of FBLD is to provide access to difficult targets, which will be explored by combining molecular docking and biophysical screening against peptide-GPCRs to identify novel lead candidates. A second challenge is that efficient treatment of neurological disorders often requires modulation of multiple targets, which also will be the focus of the project.

1 467 500 €

Start date: 2017-11-01, End date: 2022-10-31