Stem cell models of kidney development and disease, live imaging, bioinformatics

The Combes laboratory has opportunities for postgraduate research projects in animal and stem cell models of kidney development and disease, advanced imaging, single cell and spatial profiling, and bioinformatics. Prospective PhD students will be supported to apply for competitive scholarships, which are awarded on the basis of publications, research experience, and academic track record. PhD candidates within the lab are motivated, self-directed learners with effective communication skills and sound organisational abilities. Prior experience in stem cell culture, developmental biology, imaging, molecular biology, or bioinformatics is desired but we also welcome talented students from other academic disciplines. Experience in disease modelling, advanced imaging and bioinformatics gained during a PhD in the Combes lab will enable graduates to develop skills that are in high demand in academic research and industrial settings world-wide. Project outlines are listed below, please get in touch to discuss or visit our lab website for more information. Human stem cell models of kidney disease Acute kidney injury (AKI) affects over 13 million people per year, resulting in illness, high health care costs, and over 1.7 million deaths. Individuals who survive AKI often develop chronic kidney disease (CKD). There are no targeted therapies for AKI or to prevent progression to CKD, and insight into human disease mechanisms remains limited. In collaboration with clinicians and disease experts we are carefully evaluating the capacity of stem cell-derived human kidney tissue to model acute kidney injury and the transition to chronic kidney disease. In parallel we are establishing improved culture methods and assays required to facilitate high throughput drug screening. If successful, our efforts will provide a platform to accelerate target discovery and therapeutic development for acute kidney injury and aspects of chronic kidney disease. This project involves stem cell culture, disease modelling, confocal imaging, gene expression profiling, and drug screening. Engineering improved cell and tissue models of the human kidney The generation of miniature kidney ‘organoids’ from stem cells has led to considerable progress in modelling human kidney development and the genetic drivers of early-onset disease. However, improvements in the cellular composition, maturation, and patterning of kidney organoids are required to extend the impact of organoid technology to model common adult disease states and for future applications in regenerative medicine. This project aims to determine the molecular programs that control mammalian kidney development and implement this new knowledge to engineer improved stem cell models of the human kidney. We expect that this work will also identify new genetic drivers of renal birth defects and susceptibility to chronic kidney disease. Our lab uses a combination of mouse and human stem cell models of kidney development, single cell and spatial profiling technologies, imaging and bioinformatics to investigate kidney development. Individual projects in this area will focus on 1) Bioinformatic analysis of gene regulatory networks and signalling interactions controlling cell fate from single cell and spatial profiling data 2) Investigating signals and pathways predicted to regulate kidney development in stem cell and animal models, 3) Applying developmental knowledge, materials science and bioengineering principles to improve stem cell models of the human kidney. Live imaging kidney development and regeneration Our lab has pioneered live imaging methods to interrogate cellular interactions and cell movement during kidney morphogenesis. Our work to date established a new model of progenitor cell commitment and revealed new insight into the dynamic changes that occur at a cell and tissue level during kidney development. However, much remains to be discovered about how individual and collective cell movement influences organogenesis. Moreover, combining living imaging approaches with organoid models enables new opportunities to study injury and repair mechanisms in real-time. Live imaging in mammalian organ systems is in its infancy due to difficulties associated with imaging fluorescent reporters through multiple cell layers. To address this challenge, we have built a state-of-the-art super-resolution spinning disk confocal microscope ideally suited to imaging biological processes at multiple scales in living tissue and organoid models.This project will leverage our established imaging methods, cutting-edge microscope, and unique biological systems to deliver new insights into the mechanisms of mammalian organ formation, tissue injury, and regeneration.