Mechanisms of action of anabolic osteoporosis therapy: functional studies using genetically modified mouse models and lineage tracing

Applications are no longer being accepted for this project

With ageing our bones become brittle and prone to fractures, known as osteoporosis. Despite widespread use of therapies blocking bone loss, osteoporosis represents a major public health concern. There is a large clinical need for bone-building (osteo-anabolic) treatments that sustainably improve bone mass in patients. Only very few osteo-anabolic treatments are currently clinically used, including intermittent parathyroid hormone and anti-sclerostin antibodies. While they effectively stimulate bone formation, suspected side-effects and limited long-term information unfortunately limit their use. Increasing our in-depth understanding of the mechanisms of action of the currently available drugs at the cellular-molecular levels is needed to identify strategies for improved therapeutic use of existing drugs or for developing even more powerful and/or safer new treatments.

In the KU Leuven SCEBP laboratory, the research team led by Prof Maes studies the genetic and molecular control of bone development, homeostasis, repair, and disease treatment, with a key focus on the interplay between skeletal stem/progenitor cells (SSPCs) and the vasculature of the bone and marrow environment. In their previous work, they have characterized the importance of specific molecules and signalling pathways that stimulate angiogenesis (blood vessel growth) and that drive bone formation during growth and fracture repair. In the currently vacant PhD project, the student will investigate whether these pathways and the cellular communication between SSPCs and endothelial cells within the bone may work together to stimulate bone formation therapeutically.

To analyze the functional involvement of specific molecules and cells in osteo-anabolic therapy actions, the student and team will use genetically modified mouse models, including inducible and site-specific mouse mutants and transgenic mice carrying fluorescent reporters for lineage tracing and cell fate mapping in vivo, complemented with in vitro systems. The student will apply basic and advanced bone phenotyping methods, such as micro-/nano-CT, histomorphometry, high-resolution 3D confocal microscopy and image analysis, and transcriptomic profiling by single cell and bulk RNA-seq.

Project goals

Overall, this work could lead to the development of improved anabolic treatment approaches for osteoporosis.

Who we are looking for

We are looking for a bright and highly motivated PhD candidate to join our team. Fitting candidates are expected to be very engaged, pro-active and creative, eager to drive their research project, and with good critical-thinking and problem-solving abilities. The work of a PhD student includes designing research protocols, planning and performing experiments (both independently and as part of a team, with thorough training provided by experienced researchers), analyzing data, reporting results to supervisors and colleagues and discussing the findings to shape and outline the next steps. Therefore, good organisational skills, time and project management and ability to work to priorities, are required.

Good knowledge of cell and molecular biology, physiology and the basic biomedical research methodologies is necessary. Fitting candidates will hold a Masters degree in a relevant area (with a final ‘cum laude’ grade), or an equivalent diploma (e.g. Honours degree). Skills and experience in cell culture, histology, microscopy, molecular biology, transcriptomic data analysis, and/or in vivo work (especially with mice) is not expected but certainly a plus.

Excellent written and oral communication skills are essential. Demonstrated ability to write research reports (e.g., a master thesis) or other manuscripts to a publishable standard (even if not published to date) is expected.

What we offer

We offer a PhD position in an international research team, with training and supervision at multiple levels, an interesting project and state-of-the-art techniques, and numerous possibilities to further grow scientifically, including by designing and performing research, writing papers as first author, participating in international meetings, collaborating with other scientists, etc. Specifically:

• A fully funded position for 4 years, of which one year will be spent in the partner institution, with the aim of obtaining the PhD degree in both institutes.
• The candidates will be enrolled in the PhD programs of the Biomedical Sciences group at KU Leuven and of the University of Melbourne, Department of Medicine at St Vincent's Hospital.
• The starting date is flexible and determined with the selected PhD student candidates.
• The PhD candidates will benefit from the combined expertise of the project supervisors at KU Leuven and University of Melbourne, and the embedding into two research environments. The collaboration between Associate Professor Christa Maes and Professor Natalie Sims is designed to build a strong network of researchers interested in the biology of bone health and disease, in which future research work will make use of the resources developed in the current projects for other joint studies, e.g. in models of skeletal disease and repair, cancer and metastasis, and chronic kidney disease.
• The specific PhD project described here will be based at the Faculty of Medicine of the KU Leuven (with a minimum 12-month stay at the University of Melbourne) and include affiliation to the KU Leuven Doctoral School of Biomedical Sciences (https://gbiomed.kuleuven.be/english/phd).
• The SCEBP Lab at KU Leuven is integrated in the Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration. The lab is located on a large University Hospital and Health Science Campus where basic, translational and clinical research meet.
• KU Leuven is consistently ranked within the top of Europe's leading universities and English is the working language for research; for more information visit www.kuleuven.be/english/.
• The location is the vibrant city of Leuven, which has a strong international appeal, locates just 30 km east of Brussels in the heart of Europe, and is less than two hours travel from Paris, London and Amsterdam.
• The location for the University of Melbourne partnership is St. Vincent’s Institute (https://www.svi.edu.au), which is a multidisciplinary medical research institute within the St. Vincent’s Hospital campus, located walking distance from the Central Business District of Melbourne, a vibrant multicultural city and one of the most livable cities in the world.

Applications are no longer being accepted for this project