Investigating the interplay between primary cilia and metabolic rewiring in Polycystic Kidney Disease
Anne Kallehauge Nielsen (ESR6)
Anne holds a master's degree in Cellular Biology and Physiology from University of Copenhagen (2018). This is also where her passion for cell biology originates. During her master thesis project at the Neuroscience lab at Bispebjerg Hospital, Anne's interest for translational research was sparked. Here she saw how new discoveries impacts and gives knowledge to help resolve complex problems in the field of pathology.
After years of working in the industry, Anne decided to leave her job in R&D and take on a new position in the SCiLS program, leading to a cross-country move from Denmark to Italy. She enrolled in the ambitious International Cellular and Molecular Biology PhD program at Università Vita-Salute San Raffaele (UniSR), situated on the outskirts of Milan.
This decision marked the beginning of a 3-year period of studying abroad, based in the Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, under the supervision of group leader Dr. Alessandra Boletta. In this lab, she studied the relationship between cilia and metabolism and their implications in kidney diseases.
The PhD journey came to an end in January 2024, when she publicly and successfully defended her thesis in front of the scientific committee, interested internal and external colleagues, friends, and family. This marked the end of a challenging but eventful PhD era, filled with numerous achievements and a publication on the subject (*) which amongst other contained important results achieved with our partnered collaboration from the SCiLS program.
Since finishing her PhD, Anne now apply her knowledge in her new position in Clinical Affairs at the danish company, AMBU.
*Steidl, M.E., Nigro, E.A., Nielsen, A.K. et al. Primary cilia sense glutamine availability and respond via asparagine synthetase. Nat Metab 5, 385–397 (2023). https://doi.org/10.1038/s42255-023-00754-6
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) pathology is a renal ciliopathy with implications on the metabolism. In fact, a prominent feature of the disease is the rewiring of metabolic pathways. The genetic disease, most frequently caused by mutation in the PKD1 gene, leads to disruption of the Polycystin 1 (PC1) and Polycystin 2 (PC2) complex located on primary cilia in kidney cells. The exact mechanism of a defective PC1-PC2 complex downstream of the primary cilia has yet to be elucidated. However, several signalling pathways have been reported to be affected in the disease. A key player in cilia formation and intracellular signaling is the Intra flagellar Transport (IFT) complex. Deletion of various IFT proteins leads to renal ciliopathies and deletion of the IFT-B complex protein Ift88 results in a polycystic kidney disease phenotype in mice. Interestingly, preliminary results from the group of Dr. Boletta has shown that Ift88 knockout cells presents a drastic rewiring in the metabolism. The aim of this study will be to investigate the role of cilia in regulating the ADPKD metabolic alterations.
The CRISPR/Cas9 genetic editing tool will be used to generate Ift88 (IFT-B protein) and Ift140 (IFT-A protein) KO mouse IMCD cells to test the role of IFT-A and IFT-B in regulation of the metabolic changes associated with ADPKD pathology. Differences in the metabolic and transcriptomic response to metabolic stress will be measured and analyzed by using Mass Spectrometry, metabolic tracing, SeaHorse and q-PCR.
We want you to understand!
Layman abstract:
Curing sugar addiction
Polycystic Kidney Disease (PKD) is a disease caused by changes in the genes affecting kidney cells, making them grow faster and, after time, developing big cysts. Cells with changes in these genes use nutrients differently from healthy cells and have a sweet tooth for sugar. Restricting sugar usage in cells has promising results in slowing down progression of cysts. While trying to understand why some cells become sugar addicts, we started to investigate cilia. Cilia are long hair-like structures on most cells. They communicate important messages to the cells. In PKD the cilia seems to be out of order. Interestingly, we have found that cilia are involved in usage of nutrients. Therefore, my project focuses on investigating the role of cilia in sensing and using nutrients in PKD. Understanding the underlying reasons for the unhealthy diet of kidney cells in PKD could mean a promising future for new treatments within PKD.
