PhD Student in the Mechanobiology of Disease

We are looking for a motivated colleague who will develop research in the Mechanobiology of Disease team as a PhD student.

PhD topics

1. Dissection of YAP1 activity on sarcomere maturation and force generation in human cardiomyocytes
   
   Reactivation of developmental pathways is an emerging avenue in efforts to regenerate adult failing heart. Hippo pathway effector YAP1, key player during development, which is deactivated in an adult heart, is one of such targets. While the Hippo mediated (pro-proliferative) effects of YAP1 activity have been thoroughly explored, the effects of Hippo independent activation of YAP1 on sarcomere structure, maturation, and force development are just starting to be explored.
   
   The student will work with in vitro model of pluripotent stem cell derived cardiomyocytes. Initially the student will prepare inducible human pluripotent stem cell lines to 1. silence endogenous YAP1 2. induce expression of mutated variants of YAP1. Next, impact of temporally restricted expression of YAP1 variants on cardiomyocyte mechanosensing, maturation, and force production using super-resolution microscopy, traction force microscopy in single cell cultivation model will be assessed. Finally, mechanistic understanding of the process will be facilitated by identification of interactors and transcription factors mediating differential outcomes of different mutant forms of YAP1.
2. The effect of mechanical stimuli on the RNA splicing
   
   Several studies published in recent years brought evidence that RNA-splicing is altered when mechanical stimuli are applied. This is catalysed through RNA-binding proteins (mainly heterogenous nuclear ribonucleoproteins, hnRNPs, and serine/arginine-rich proteins, SR) that play a major role in splicing regulation. The process is closely related to three-dimensional spatial re-organization of splicing regulators. Recent data also associate the abnormal regulation of alternative splicing to the occurrence and development of tumors and therapeutic approaches based on targeting the splicing machinery emerge. Tumors display altered mechanical properties compared to healthy tissues that reflect into changes in proliferation, apoptosis, invasion, metastasis, angiogenesis, and metabolism of the tumor cells.

The overall aim of the doctoral thesis is to elucidate the relationship between mechanical signalling and splicing regulation. This topic is novel and ambitious with possible outcomes ranging from describing mechanisms fundamental for cellular biology in the early stages of development to the new inights into the regulation in cancer cells.

The International Clinical Research Centre of St. Anne's University Hospital in Brno (ICRC) is a leading scientific research centre in Central Europe with more than 400 researchers. We focus on research and development, particularly in the field of cardiovascular, and neurological diseases, and oncology in an effort to find new ways to prevent, diagnose and treat these diseases.

MECHANOBIOLOGY OF DISEASE
https://www.fnusa-icrc.org/en/research/research-teams/pre-clinical-research/mechanobiology-of-disease/

Join us and take your career a step further!

We offer:

• Working in a dynamic experienced team in an international environment
• Well-equipped laboratories, good publication prospects
• Contribution to solving the major health problems of today
• Adequate salary conditions
• Half-time employment for the duration of the study and a Ph.D. scholarship
• Possibility to apply for additional personal scholarship (https://www.jcmm.cz/projekt/brno_phd_talent/)

Expected date of entry: 1. 3. 2025 or by agreement

What qualities, knowledge and skills we expect:

• Knowledge of English language at the level of normal communication, presentation of results and study of literature
• Master's degree in natural or medical sciences
• Experience working with mammalian cell cultures is an advantage
• Knowledge of basic molecular biology methods an advantage: e.g. fluorescence microscopy, RT-qPCR, Western Blotting
• Experience in data processing is an advantage: e.g. in R or Python
• Willingness to learn new methods and critical analysis of research data
• Ability to solve research questions independently, but also willingness to learn from more experienced people in and outside the team
• Enthusiasm for translational research