Brain structure determines function. Disentangling regional microstructural properties and understanding how these properties constitute brain function is a central goal of neuroimaging of the human brain and a key prerequisite for a mechanistic understanding of brain diseases and their treatment. Using magnetic resonance (MR) imaging, previous research has established links between regional brain microstructure and inter-individual variation in brain function, but this line of research has been limited by the non-specificity of MR-derived markers. This hampers the application of MR imaging as a tool to identify specific fingerprints of the underlying disease process. Exploiting state-of-the-art ultra-high field MR imaging techniques, I have recently developed two independent spectroscopic MR methods that have the potential to tackle this challenge: Powder averaged diffusion weighted spectroscopy (PADWS) can provide an unbiased marker for cell specific structural degeneration, and Spectrally tuned gradient trajectories (STGT) can isolate cell shape and size. In this project, I will harness these innovations for MR-based precision medicine. I will advance PADWS and STGT methodology on state-of-the-art MR hardware and harvest the synergy of these methods to realize Cell-specific in-vivo MORPHOMETRY (C-MORPH) of the intact human brain. I will establish novel MR read-outs and analyses to derive cell-type specific tissue properties in the healthy and diseased brain and validate them with the help of a strong translational experimental framework, including histological validation. Once validated, the experimental methods and analyses will be simplified and adapted to provide clinically applicable tools. This will push the frontiers of MR-based personalized medicine, guiding therapeutic decisions by providing sensitive probes of cell-specific microstructural changes caused by inflammation, neurodegeneration or treatment response.

Every year nearly 228,000 individuals die from colorectal cancer (CRC) in Europe, the second most common cancer in Europe. Around 30% of the CRC patients develop liver metastases and these are the main cause of death. Removal of liver metastatic tumors is the primary treatment method for CRC, however, 50-75% of the patients experience a relapse of the metastases within two years, rendering adjunct treatment strategies necessary for these patients. Preclinical work has demonstrated that exercise exerts anti-tumor effects as it is indeed able to inhibit tumor growth. Thus, exercise constitutes an excellent candidate as a complementary to the pharmacological treatment approach for CRC metastatic patients (mCRC). My primary aim is to investigate the effects of chronic exercise on tumor recurrence after liver metastasis removal. Secondary aims are to identify the “optimal dose” of exercise to obtain the largest beneficial effect and explore the changes on circulating tumor DNA (ctDNA) as a marker of disease progression. I hypothesize that exercise training will delay or ameliorate disease recurrence in mCRC patients. Patients will be randomized to 3 groups: control, group 1(300 min/week), group 2 (150 min/week) of combined aerobic and strength exercise training for 6 months. Study endpoints will be tumor recurrence, inflammation and immune markers, physiological adaptations and ctDNA changes. The outcomes will provide essential knowledge about how to optimize the guidelines for exercise prescription as part of the treatment plan for mCRC patients. The fellowship will be vital for my reintegration into academia and for me to evolve as a lead researcher. It also constitutes an ideal means of knowledge transfer between myself and the host organization as I will gain knowledge in the oncology area and advance my skills in molecular biology techniques while I convey my experience in dose-response methodology and the conduct of large-scale human exercise trials.

Cancer Immunotherapy is the latest breakthrough in the fight against cancer, especially with the successes of checkpoint inhibitors. However, numerous tumors appear non-responsive, including uveal melanoma (UM) despite its shared cellular origin with cutaneous melanoma. In this project, I propose to study the immune landscape of UM and explore strategies to overcome mechanisms detrimental to the antitumor immune response. I will employ highly innovative technologies from the fields of genomics, immunology and bioinformatics to explore the tumor microenvironment. Gene expression profiles of UM metastases and neoantigen presentation will be obtained by RNA sequencing. The functional expression of multiple immune markers will be analyzed by cutting-edge multispectral immunohistochemistry to determine immune cell subset presence in a qualitative and quantitative manner. The obtained knowledge will subsequently be used to test and improve reactivity of tumor-infiltrating lymphocytes in an autologous model. These experiments require optimal expansion of tumor-infiltrating T cells, which is highly developed at the laboratory of prof. Svane at the Center for Cancer Immune Therapy at the Herlev Hospital in Copenhagen, Denmark. I expect that this project will provide a more complete overview of the immune landscape of UM and reveal important mechanisms underlying immune suppression in UM. The findings of this project could pave the way to the clinical development of successful immunotherapeutic strategies for the treatment of UM and potentially other tumor types resistant to immune checkpoint inhibitors. Finally, this project will improve my laboratory and leadership skills, greatly improving my chances of achieving the next goal in my career: a permanent position as an Medical Oncologist with my own lab-based group in the expanding field of Cancer Immunotherapy to accelerate the application of translational research into the clinic.

Multiple sclerosis (MS) is a diffuse inflammatory and neurodegenerative disease of the central nervous system. Neuroinflammation destroys the myelin sheaths wrapped around the axons and may lead to axon degeneration. Repair processes trigger re-myelinisation. Myelin loss delays or blocks signal propagation along axons in white matter tracts, impairing neuronal integration within the affected brain network. The exact relationship between the amount of axonal de- and re-myelination and the resulting network dysfunction is still poorly understood. Using a rat MS model, I will bridge the scales from the cellular to the network level, to disentangle how myelin loss and axonal degeneration leads to network dysfunction. My approach integrates three lines of research: (i) I will prospectively perform diffusion MRI and quantitative MRI to assess the temporal dynamics of microstructural changes in axon diameter and myelin content in the lesioned white matter tract. Leveraging state-of-art expertise at DRCMR, I will optimize MR sequences and biophysical models to create an optimized axon diameter and myelin mapping framework. (ii) In parallel, I will perform resting-state and task-based functional MRI to trace the resulting changes in functional connectivity at the network level. (iii) Building on my expertise, I will combine functional MRI with optogenetics and simultaneous intracellular calcium (and trans-membrane voltage) recording to characterize in detail the functional impact of axonal damage in the lesioned white matter tract on well-defined cell circuits in the inter-connected cortical areas. This unique multimodal approach will yield novel MRI-based biomarkers that are sensitive and specific to primary demyelination and axonal degeneration on the one hand and reparatory processes such as remyelination on the other hand. These biomarkers will have great potential for monitoring disease activity, informing personalized treatment in patients with MS.