B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive. Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers. We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance. We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.

The incidence of autoimmune diseases including multiple sclerosis is dramatically increasing. While there is a genetically defined “bedrock” susceptibility to develop T cell mediated autoimmunity, environmental cues likely determine the threshold for disease development. Yet, little is known on how environmental cues sensed at body/environment interfaces are translated into immunopathology in distant organs like the central nervous system (CNS). Here, we raise the hypothesis that immune cells must be activated at epithelial surfaces and then physically migrate to distant organs in order to induce autoimmunity. Furthermore, we propose that the “state of activation” of (either lymphoid or myeloid) immune cells can be interrogated by IL-6 production since IL-6 deficiency confers resistance to virtually any organ specific autoimmune disease and we have contributed fundamentally in defining the role of IL-6 for the generation of Th17 cells that are highly associated with autoimmune tissue inflammation. In EXODUS, we will develop ground-breaking next generation reporter tools in order to test these hypotheses. A split Cre recombinase protein, which dimerizes and is activated by blue light, will be used to genetically label cells (and their progeny) in a topologically defined manner (“compartment reporter”). Furthermore, we have developed a novel type of Cre-inducible in vivo IL-6 reporter (“activation reporter”). The combination of these tools will enable us to trace the anatomical compartment of activation of immune cells without limitations in lag time. Thus, site specific photogenetic co-induction of a fluorescence and IL-6 reporter will be used to probe peripheral sites for their potency to licence immune cells to travel to the CNS (Forward). Vice versa, labeling of cells in the CNS (through a thinned skull window) will allow for studying immune cell exodus from the CNS in homeostasis and during inflammation (Reverse).

Chronic back pain is a major burden and source of disability worldwide. It is primarily attributed to different biomechanical factors, but can also have inflammatory, neurological or psychological causes. Clinical findings and conventional imaging cannot reliably distinguish different causes of back pain. In contrast, individual biomechanical models can quantify diverse (pathologic) loading patterns and thus could be used to distinguish different aetiologies of back pain, to better understand individual pathophysiology and guide preventive strategies. During my recent ERC-StG “iBack”, I developed quantitative imaging methods and deep-learning based image processing to automatically generate a fully individualized biomechanical model of the thoracolumbar spine. Simultaneously, two large-scale epidemiologic studies collected clinical and high-resolution imaging data of the spine of more than 15,000 participants so far, aiming at more than 35,000 participants by mid 2022 The high-level objective of iBack-epic is to use such novel image analysis techniques to identify different biomechanical and inflammatory causes of back pain in study participants. I will adopt and extend my recently developed deep-learning based spine labelling and segmentation algorithms to fully automatically calculate individual biomechanical, functional and morphometric parameters of the spine. In this large-scale population data, I will identify different biomechanical loading patterns, use quantitative image-based parameters to discriminate normal ageing from pathologic degeneration and identify pathological conditions that are linked to back pain or subsequent development of chronic back pain. Such a differentiation – for the first time based on quantitative image data – will allow for a better understanding of the underlying pathophysiology of back pain, an improved risk stratification, a tailored investigation of genetic causes and thus will help to better guide preventive strategies.

Alzheimer’s disease (AD) is the most prevalent deadly neurodegenerative disorder for which no effective treatment exists as of today. Therefore, there is an urgent need to better understand the molecular mechanisms behind AD in order to develop more effective treatments against this complex disease. Recent genetic findings have highlighted several AD-associated genes, many of which are preferentially expressed in microglia in the brain. One of these is tetraspanin 14 (TSPAN14), whose physiological function in the brain is not yet understood. Recent studies suggest that TSPAN14 may act as a functional regulator of ADAM10, a transmembrane protease that cleaves multiple substrates in the brain including the AD-associated protein TREM2. Full-length TREM2 is essential for the phagocytic activity of microglia and its cleavage by ADAM10 results in loss of function. The central aim of the TSPAN14-AD project is to understand how TSPAN14 controls molecular pathways involved in AD, by focusing on proteolysis and function of TREM2. Specifically, we hypothesize that TSPAN14 increases AD risk by modulation of TREM2 cleavage and microglial phagocytosis. The 3 objectives of TSPAN14-AD are to: (1) determine whether AD-protective TSPAN14 alternative splicing variants result in reduced TSPAN14 protein expression; (2) elucidate whether reduced TSPAN14 expression results in decreased ADAM10 cell surface expression; (3) assess whether loss of TSPAN14 reduces TREM2 cleavage and enhances phagocytic activity of microglia. To accomplish this, a combination of biochemical, molecular, and proteomic techniques will be used within both in vitro and in vivo models, including human induced pluripotent stem cell (iPSC)-derived microglia and post-mortem human brain tissue. Outcomes of the project have the potential to fill in a large gap in our current understanding of molecular mechanisms leading to AD pathogenesis and may provide insight into novel therapeutic targets for AD and related disorders.