A global understanding of therapy response and therapy resistance in haematologic malignancies, including multiple myeloma and acute lymphoblastic leukaemia, in which cancerous cells accumulate in the bone marrow, is still lacking. This is due to the complex nature of the bone marrow. Therefore, the goal of SESAHME is to determine the difference of the bone marrow microenvironment in healthy individuals and patients suffering from multiple myeloma and acute lymphoblastic leukaemia. This will help to understand under which conditions cancerous cells can accumulate and proliferate in the bone marrow which could lead to advanced immunotherapy approaches in the future. To achieve this, the objectives of SESAHME are to 1) establish a method that allows to determine the immune microenvironment composition in human formalin-fixed paraffin-embedded samples of the bone marrow, which has the potential for high-throughput screening and being cost effective at the same time; and 2) to use this method to characterise a healthy and dysfunctional bone marrow microenvironment that can contribute to multiple myeloma/acute lymphoblastic leukaemia development and progression. SESAHME will allow the fellow to independently carry out a project which will set the ground to build upon an own, individual research profile to eventually become an independent researcher. Key transferable training will further improve the employability and career prospects of the fellow, as well as increase the fellow’s communication abilities. The host offers a multi-disciplinary environment that is well connected with experts in the field enabling the fellow to develop a new mindset and approaches. The fellow brings international and specialised wet-lab experience that will facilitate knowledge exchange and increase R&I capacity. Finally, SESAHME will increase the global attractiveness of the host via concrete dissemination activities.

Sporozoites are the motile forms of the malaria causing parasite Plasmodium and are injected into the vertebrate host by a mosquito. Their motility is powered by the parasites own actin-myosin motor, which is connected to transmembrane proteins of the TRAP (thrombospondin-related anonymous protein) family which serve as force transmitters. This substrate-dependent locomotion is a prerequisite for tissue penetration and host cell invasion. The glycolytic enzyme aldolase was thought to be the link between actin and surface adhesins (reported in Mol Cell). However, recent data revealed that aldolase does not fulfil this role hence it is now unclear how the force is transmitted. Additionally, lack of the main surface adhesin TRAP was also found (by the host lab) to not block motility as previously reported (in Cell). Additional recent findings are challenging the model of how gliding motility works and thus highlight the importance to focus on novel proteins. One such new protein, LIMP has recently been identified in the host lab. Therefore, the principal aim presented in this proposal is the identification of the molecular function of LIMP, which shows an identical phenotype to TRAP. To this end I will generate a series of parasites strains expressing different mutated versions of LIMP which will be investigated using biophysical approaches. Moreover, I attempt to identify the proteins interacting with LIMP.

Addiction to drugs is a ubiquitous neuropathological disease that inflicts immense societal costs. A core aspect of addiction that poses a major challenge for treatment is the propensity to relapse in environmental contexts that are associated with drug use. Identification and mechanistic characterization of novel addiction-relevant circuitry linking the motivation to take drugs to the complex spatial and non-spatial features that constitute a drug-associated context are at the core of this proposal. These insights will be used to identify the best constellation of anatomical targets to prevent and reverse the expression of context-triggered drug-seeking. The medial and lateral entorhinal cortex (MEC and LEC) are two central components of the episodic memory system integrating all features relevant for the formation of contextual memory. Crucially, MEC and LEC receive strong bottom-up dopaminergic input from the midbrain and send top-down projections to the nucleus accumbens (NAc). The dopaminergic system is the primary target of all addictive drugs. We will 1) study how bottom-up dopaminergic projections are implemented into drug-context associations in MEC and LEC and 2) determine how these associations influence NAc-mediated drug-seeking behaviour. We will utilize a multidisciplinary approach by developing electrophysiological in vivo recording paradigms in behaving mice that allow the assessment of complex spatial, contextual and non-spatial codes in conditioned place preference and self-administration paradigms typically used to model addiction in rodents. This will be combined with optogenetically-assisted circuit analysis of molecularly-defined pathways to link identified functions to the underlying circuitry. Pathway-specific optogenetic silencing will be used to prevent and reverse the manifestations of drug use on a neuronal and behavioural level. This will guide the evidence-based development of therapies in the future, such as deep-brain stimulation.