ERC FUNDED PROJECTS

My recent discoveries show that mosaic loss of chromosome Y (LOY) in peripheral blood is associated with increased risks of cancer and Alzheimer’s disease (AD). These conditions are responsible for >50% of morbidity/mortality in aging men. More than 15% of men older than 70 show some degree of LOY and these men survive on average only half as long as men without LOY. Smoking is strongly associated with LOY and remarkably, the fraction of cells with LOY decreases after cessation of smoking. Cells with LOY can be detected, and disease risks predicted, many years before clinical manifestation of disease. These results of associations between LOY, cancer and smoking have been published in Nature Genetics and Science during 2014. The overall objective of the proposal is to develop LOY as a new, strong and predictive biomarker. To this end, the research program focuses on three objectives: 1) expanding the study of LOY and associations with disease risks in still larger cohorts; 2) investigating functional aspects of LOY; and 3) develop improved technology for LOY-detection. The successful execution of the project is essential before LOY-testing in clinics can be realized. Diagnosis of cancer and AD in modern medicine is based on clinical symptoms of disease. Through earlier identification of individuals at increased risk for disease, preventive strategies could be applied, before the severe stages appear. Preliminary results affirm the feasibility of the project and provide proof-of-concept that LOY-tests can be used for early identification of men with increased risks for these diseases. In addition to improving diagnostics and therapeutics; implementation of LOY-testing could prevent smoking-related disease and reduce the health care costs. In the end, LOY-testing could decrease male mortality rates and possibly eliminate the sex-difference in life expectancy. The project will therefore benefit individual patients as well as healthcare systems and society at large.

1 525 000 €

Start date: 2016-03-01, End date: 2021-02-28

Oligodendrocytes (OL) are glial cells that mediate myelination of neurons, a process that is defective in multiple sclerosis (MS). Although OL precursor cells (OPCs) can initially promote remyelination in MS, this regenerative mechanism eventually fails in progressive MS. OPCs go through several epigenetic states that ultimately define their potential to differentiate and myelinate. OPCs in progressive MS stall in a distinct epigenetic state, incompatible with differentiation and remyelination. We hypothesize that these OPCs regress to an epigenetic state reminiscent of the state of embryonic OPCs, which remain undifferentiated. In this proposal, we aim to uncover the causes behind the remyelination failure upon disease progression in MS. We will determine the epigenetic/transcriptional states of OPCs during development and in MS, using single cell and bulk RNA sequencing and quantitative proteomics. We will further investigate how the interplay between transcription factors (TFs), chromatin modifiers (ChMs) and non-coding RNAs (ncRNAs) contributes to the transition between epigenetic states of OPCs. The results will allow the identification of ChMs and ncRNAs that can modulate these states and thereby control OPC differentiation and myelination. We will use this knowledge to investigate whether we can reverse the epigenetic state of OPCs in MS, in order to promote their differentiation and remyelination. The unique combination of leading-edge techniques such as SILAC coupled with immunoprecipitation and mass-spectrometry, single-cell RNA sequencing, ChIP-Sequencing, among others, will allow us to provide insights into novel epigenetic mechanisms that might be underlying the effects of environmental and lifestyle risk factors for MS. Moreover, this project has the potential to lead to the discovery of new targets for epigenetic-based therapies for MS, which could provide major opportunities for improved clinical outcome of MS patients in the near future.

1 895 155 €

Start date: 2016-09-01, End date: 2021-08-31

Proposal summary Type 2 diabetes and cardiovascular disease are devastating and costly morbidities whose prevalences are increasing rapidly around the world. As such, there is an urgent need to develop innovative and effective prevention and treatment strategies. As numerous clinical trials have shown, lifestyle modification is by far the best way to prevent these diseases, with lifestyle being twice as effective as the best drugs, less costly and free from side effects. Yet, human biology is complex, causing some people to respond well and others poorly to the same lifestyle interventions. Thus, a huge, as yet unrealised opportunity exists to optimize the prevention and treatment of cardiometabolic diseases by tailoring lifestyle interventions to the patient’s unique biology. NASCENT is an integrated programme of research through which I will functionally annotate and later translate discoveries of gene-lifestyle interactions made through the interrogation of large epidemiological (N>100,000) datasets at my disposal. The functional annotation of these discoveries will be done using state-of-the-art epigenomic and targeted gene editing tools, whereas the translation of those findings will be achieved using a innovative and powerful clinical trial design that focuses on treatments that are tailored to the participant’s genotype (genotype-based recall). NASCENT capitalizes on a solid foundation of cohorts, methods, and expertise that I have built-up over the past fifteen years, but also exploits state-of-the-art epigenomic and gene-editing technologies that have not previously been used in studies of gene-lifestyle interactions. I expect the integration of these established and new approaches in NASCENT to propel major advances in understanding gene-lifestyle interactions in cardiometabolic disease that help optimise disease prevention.

1 875 000 €

Start date: 2017-02-01, End date: 2022-01-31

Critical to our understanding of Alzheimer’s disease (AD) and also to finding therapies is determining how key pathological factors interact and relate to neuronal toxicity, symptoms and disease progression. My research has focussed on amyloid beta (Aβ) moities and demonstrated that cerebrospinal fluid (CSF) Aβ42 correlates with cerebral Aβ pathology; that Aβ accumulates in the brain 10-20 years prior to onset of symptoms; and that CSF Aβ abnormalities precede CSF tau changes. However, it is increasingly clear that a simple linear model of AD aetiology and progression is inadequate. This proposal aims at developing and validating new diagnostic and prognostic biomarker tools to examine the AD pathogenesis in humans taking a broad view of AD’s multiple pathophysiological features and their putative biomarkers. The major questions, all relevant to therapeutic research, that will be addressed in my proposal include: (i) how are different forms of Aβ produced and modified; (ii) what is the toxicity of these different forms; (iii) how is this toxicity mediated; and iv) what other pathologies may contribute to or modify AD-like phenotypes? We and others have shown that Aβ monomers are relatively non-toxic. We will address the hypothesis that Aβ starts to accumulate in the brains of certain individuals due to defective clearance of the peptide. Once aggregated, Aβ acquires chemical modifications during brain incubation over years. These modified Aβ forms then induce tau hyperphosphorylation and concomitantly over-activate the immune system, resulting in neurotoxicity. Other pathologies, including α-synuclein and TDP-43, may contribute in this process. In PATHAD, we will develop and validate new diagnostic and prognostic tools using a combination of groundbreaking technologies and unique clinical materials to dissect the underlying molecular pathogenesis of AD in much greater detail than what has been possible before and facilitate the development of effective treatments.

1 985 093 €

Start date: 2016-12-01, End date: 2021-11-30