Kennedy Trust Prize Studentships
Identifying novel therapeutic targets in fibrotic diseases
Fibroproliferative disorders result in significant morbidity and, in many instances, mortality, contributing to 45% of deaths in the USA. The molecular mechanisms underlying pathological fibrosis remain poorly understood, hindering therapeutic progress. However, it is now increasingly appreciated that myofibroblasts are responsible for the excessive and disordered matrix production and contraction in all cases of pathological fibrosis. Currently effective strategies for targeting this cell remain elusive1. Challenges include limited access to diseased human tissue, especially in the early stages and the lack of appropriate animal model as they rely on administration of toxins, which are rarely encountered in clinical practice. Study of primary human tissues in our laboratories has led to identification of a novel therapeutic target and a phase II clinical trial for Dupuytren's disease, a localised fibrotic disorder. The myofibroblast phenotype is altered by passage in culture and when they are subjected to unphysiological mechanical stresses. Furthermore, there is a complex interplay between the stomal and immune cells which drives the chronic inflammatory and fibrotic response2. To quantify the mechanical stress generation in myofibroblasts under physiological conditions, we recently developed the novel method of STFM (super-resolved traction force microscopy)3. This project aims to identify novel therapeutic targets for down-regulating the myofibroblast phenotype using primary cells from samples from patients with a range of fibrotic diseases by combining STFM with assays already well established in our labs. We will initially investigate the localised fibrotic disorders (Dupuytren's, endometriosis) and then extend our studies to visceral fibrotic diseases, including liver fibrosis.
You will be based in the new, purpose built labs at The Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation. In the first term you will attend 20 core lectures. Throughout your studentship we will encourage you to attend weekly seminars at the Institute given by global leaders in the fields of immunology and cytokine biology. You will benefit from combined supervision by a biophysicist with expertise in advanced biophysical techniques, including STFM, and two clinician scientists through weekly lab meetings, where students and post-doctoral scientists discuss their findings. You will also gain invaluable experience in writing manuscripts for publication and presenting at conferences. There is support available from post-doctoral scientists in our groups and lab managers to become proficient in cell and molecular biological techniques, advanced biophysical and microscopy techniques including super-resolution stimulated emission depletion microscopy, atomic force microscopy, and STFM, tissue culture, ELISA/electrochemiluminescence, immunohistochemistry and RT-PCR. Overall, the Kennedy Institute provides an ideal environment for intellectual development and translational research.
- Nanchahal J, Hinz B. Strategies to overcome the hurdles to treat fibrosis, a major unmet clinical need. Proceedings of the National Academy of Sciences of the United States of America 2016; 113:7291-3
- McGettrick HM, Butler LM, Buckley CD, Rainger GE, Nash GB. Tissue stroma as a regulator of leukocyte recruitment in inflammation. J Leukoc Biol 2012; 91:385-400.
- Colin-York H, Shrestha D, Felce JH, Waithe D, Moeendarbary E, Davis SJ, Eggeling C, Fritzsche M. Super-Resolved Traction Force Microscopy (STFM). Nano Lett 2016, 16: 2633-8.
Translational Medicine and Medical Technology; Molecular, Cell and Systems Biology; Geratology and Degenerative Diseases; Musculoskeletal Science.
Dr Marco Fritzsche, Kennedy Institute, University of Oxford