Supervisor: Todd Alexander
Project: Mutation of the little known SVEP1 gene causes rickets because of low blood phosphate levels
Bachelor of Science with Honors in Physiology
How would you describe your research project to someone without a scientific background in one or two sentences?
My research project centers around the gene, SVEP1, which we hypothesize increases levels of the hormone FGF23, resulting in childhood rickets. By having cells overexpress this gene, we can test our hypothesis by measuring levels of FGF23, which we predict will be increased. Eventually, we can use the cell line as a tool to test new therapies.
What's been the best part of your experience so far?
The best part of the summer studentship experience so far has been the cell culture work. This is the first time I have worked with cells and it is completely different from every other technique in the lab as it involves microscopy on live samples. Cell cultures are key tools that allow us to test changing conditions with minimal risk to eventually help patients. They come with a brand new set of challenges that I enjoy tackling and working through with the guidance of professionals in my lab.
What impact do you hope this project makes once completed? How will this contribute to improving the health of children?
This project stems from a real patient who was nine years old when she was first diagnosed with childhood rickets due to a mutation in our gene of interest, SVEP1. We hope that the research done in this project will help explain the role of SVEP1 in bone mineral homeostasis. Childhood rickets is a terrible disease and we hope to benefit young patients by better understanding its genetic cause, as well as creating new tools to test possible therapies.
What interested you in the WCHRI Summer Studentship Program?
As the Physiology Honors program heavily focuses on research, I wanted to experience first-hand how research work was conducted. I learned through several summers of working with the Alexander Lab that research takes on a variety of forms, both in-person and in silico—performed on computer or via computer simulation. This summer I wanted to continue my guided learning and experience here in the lab and the WCHRI Summer Studentship Program has allowed me to do so.
What's one piece of advice you received from your supervisor/mentor that resonated with you?
Through several summers of working in the lab, my supervisor has helped me realize that science is a continuous process and that things will take time. In the conventional school system, we subconsciously assign an end date to every part of our lives. For example, the idea that I will finish my degree within four years. However, my supervisor and the research conducted here in the lab have shown me that there is no end date to discovery. There will always be more experiments to conduct and more papers to write but it is a process and rushing will often result in a worse result. Part of what makes science so interesting is that it is a field that continues to expand without an end in sight.
What has the support from WCHRI and Stollery Children's Hospital Foundation meant to you?
My research concerns a gene mutation that relates to a disease that impacts a significant number of children around the world—rickets. Childhood diseases such as rickets often impact not just the child, but also the family and community. Support from medical research often places the most vulnerable—women and children—aside whereas WCHRI, the Stollery Children's Hospital Foundation and the Alberta Women's Health Foundation have made them a priority. The support from these organizations has encouraged me to pursue this line of research for the most vulnerable, and I am grateful for the funders' commitment and enthusiasm in supporting life-changing research.
The PHEX gene is involved in regulating phosphate levels and mutations in the gene may lead to excess phosphate in the urine. This loss of phosphate causes the childhood disease rickets, which leads to poorly mineralized bones. However, a nine-year-old female with significantly elevated urine phosphate levels surprisingly lacked a mutation in PHEX and other lesser-known genes causing this disorder. Furthermore, like patients with PHEX mutations, she had inappropriately increased levels of a hormone produced by bone cells which were responsible for her increased urinary phosphate excretion and consequently poorly mineralized bones. This hormone, fibroblast growth factor 23 (FGF23), is involved in phosphate and vitamin D homeostasis. Sequencing the genes of the girl, as well as those of her parents, identified nine new mutations, but only one in a gene expressed in bones—SVEP1.
We hypothesize that SVEP1 regulates FGF23 production and prevents its excretion from bone cells. More specifically, we predict that in cells where SVEP1 expression is reduced, FGF23 production and release from bone cells will increase and in cells where SVEP1 expression is over-expressed, FGF23 levels will decrease. The cell lines with reduced SVEP1 expression will also demonstrate a reduced ability to mineralize bone. To test our hypothesis, we will use these different cell lines and measure the amount of FGF23 secreted, as well as gene expression and protein localization.
Through this research, we hope to demonstrate that a mutation in SVEP1 increases FGF23 excretion and thus increases urine phosphate levels and rickets. This work will provide answers for clinicians and the patient's family regarding the cause of her disorder and also provide a valuable tool—cell lines—to test therapies on.