Common mechanisms and pathways in Stroke and Alzheimer's disease. It has long been recognized that stroke and (Alzheimer’s Disease) AD often co-occur and have an overlapping pathogenesis. As such, these two diseases are not considered fellow travelers, but rather partners in crime. This multidisciplinary consortium includes epidemiologists, geneticists, radiologists, neurologists with a longstanding track-record on the etiology of stroke and AD. This project aims to improve our understanding of the co-occurrence of stroke and AD. An essential concept of our proposal is that stroke and AD are sequential diseases that have overlapping pathyphysiological mechanisms in addition to shared risk factors. We will particularly focus on these common mechanisms and disentangle when and how these mechanisms diverge into causing either stroke, or AD, or both. Another important concept is that mechanisms under study will not only include the known pathways of ischemic vasculopathy and CAA, but we will explore and unravel novel mechanisms linking stroke and AD. We will do so by exploiting our vast international network in order to link various big datasets and by incorporating novel analytical strategies with emerging technologies in the field of genomics, metabolomics, and brain MR-imaging.

The aim of the research is to study the effects of smallest traffic related ultrafine- or nanoparticles beyond the lung on brain health. Air pollutants have been shown to cause a vast amount of different adverse health effects. These effects include impairment of many respiratory (e.g. asthma, COPD) and cardiovascular (ischemic heart disease, infarction, stroke) diseases. However, in recent years, the evidence showing effects beyond the lungs and circulatory system are becoming more evident. Neurological diseases, namely Alzheimer´s disease (AD) has shown to be associated with living near traffic. However, reason for this has remained unresolved until today. This consortium aims on revealing the mechanisms and exposures both behind cardiorespiratory diseases and beyond the current knowledge in neurological diseases. This consortium includes experts in areas of aerosol technology, emission research, engine and fuel research, human clinical studies, epidemiology, emission inventories, inhalation toxicology, neurotoxicology and disease mechanism studies. This enables research of resolving the effects of nanoparticles from different traffic modes for both air quality and concomitant toxic effect of these air pollutants. In this study, we will investigate adverse effects of air pollutants using cell cultures, animal exposures and volunteered human exposures as well as the material from epidemiological cohort study. These are going to be compared according to inflammatory, cytotoxic and genotoxic changes and furthermore beyond the current state of the art to neurotoxic and brain health effects. With this approach, we are aiming in to a comprehensive understanding of the adverse effects of nanoparticles from traffic. In current situation only particles above 23nm are measured in regulations, traditional toxicological methods are used in risk assessment and emission inventories and regulations are largely based on old technology engines. Our project will change this.

A dysfunction of cells lining the inner walls of blood vessels, i.e. the endothelium, is the primary cause of many lifestyle related diseases. According to the WHO, those diseases accounted for 60% of all deaths worldwide in 2005. Tailor-made diagnostic tools for early and reliable identification of endothelial dysfunction are urgently needed both in fundamental research and clinical routine, respectively. The Marie Skłodowska-Curie action LOGIC LAB objects to develop and characterize innovative molecular logic gates that can be applied as advanced diagnostic tools for parallel analyte sensing in live mammalian cells. Thereby, providing a unique method to discover endothelial dysfunction and the onset of diseases much easier and earlier than so far. LOGIC LAB creates a multi-faceted and multi-sectoral research environment for the next generation of scientists in order to establish a novel type of molecular logic sensors that reliably operate in biological media – a crucial requirement for their application i.e. as rapid and easy-to-handle tools for intracellular diagnostics. With excellent cross-disciplinary scientific and complementary training provided in the network, we aim to educate highly-skilled young scientists in the fields of chemistry, physics and biology, who will significantly strengthen the international research community in the domain of molecular logic sensing. Thus, in the long term, LOGIC LAB aims to finally bridge the gap between lab bench and biological or medical practice. It is this gap, that so far prevents a wide-ranging use of existing molecular logic gates e.g. for the diagnosis of lifestyle-associated diseases.

MIMIC is an interdisciplinary European Industrial Doctorate at the interface of cell biology, engineering and drug development. MIMIC aims to develop and improve novel “organs on chips” technology. This technology combines modern cell biology with microfluidics and chip-based techniques with the goal to mimic organ functionality. There is a high demand by the pharmaceutical industry for more reliable tissue models to test drug toxicity and drug efficiency at early stages of drug development. Early reliable drug testing will have a major impact on drug development costs and human health. Furthermore, ethical considerations urge for the search for alternatives to replace animal tests in drug development and basic research. Organs on chips are a new exciting possibility to closer mimic human organ functionality in vitro than conventional 2D or 3D cell cultures. Organs on chips allow both, the emulation of healthy organs as well as the emulation of specific disease conditions using corresponding engineered or patient derived human cells. Moreover, organs on chips are ideally suited for high-throughput drug screening. The EID-MIMIC will develop novel organs on chips prototypes, and validate their suitability for end-users for high throughput drug screening or basic research. MIMIC will train early stage researchers in cutting edge technologies, like novel chip based technologies e.g. cell micropatterning, soft-lithography and microfluidics technology, as well as state of the art microscopy like super resolution- and confocal spinning disc microscopy and modern genome editing techniques like CRISPR-technology. In addition, MIMIC has developed a 3 year modular curriculum including workshops on creativity and business skills, summer schools, business plan competitions and international conferences with a specific agenda of transferable skill training elements highly relevant for scientific communication, translational research and, in particular, entrepreneurship.

The overall objective of this project is to identify novel drug candidates capable of slowing down the progression of neurodegeneration in the subset of Parkinson’s disease (PD) patients with overt mitochondrial dysfunction. Multi-modal phenotypic characterisation of cohorts of monogenic PD patients with overt mitochondrial dysfunction will be used as an anchor for the discovery of two extreme cohorts of idiopathic PD patients: with and without detectable mitochondrial dysfunction. A suite of personalised in vitro, in vivo, and in silico models will be generated using induced pluripotent stem cells (iPSCs) from selected subjects and controls. An industrial quality 3D microfluidic cell culture product, specifically designed for the culture of iPSC-derived dopaminergic neurons, will be developed for use in a morphological and bioanalytical screen for lead compounds reduce mitochondrial dysfunction. By monitoring motor behaviour and in situ striatal neurochemistry at high temporal resolution, the in vivo response to lead compounds will be characterised in humanised mouse models with striatally transplants of iPSC-derived dopaminergic neurons derived from PD patients. Personalised computational models of dopaminergic neuronal metabolism and mitochondrial morphology will be developed. These in silico models will be used to accelerate drug development by prioritising pathways for metabolomic assay optimisation, stratifying idiopathic PD patients by degree of mitochondrial dysfunction, predicting new new targets to reduce mitochondrial dysfunction and mechanistic interpretation in vitro and in vivo experimental results. SysMedPD unites a highly experienced multidisciplinary consortium in an ambitious project to develop and apply a systems biomedicine approach to preclinically identify candidate neuroprotectants, for the estimated 1-2 million people worldwide who suffer from PD with mitochondrial dysfunction.