Awardees
 

Supervisor(s):  Anna Greka
Award:  KRESCENT Post-Doctoral Fellowship
Institution:  Broad Institute (Eli and Edythe L. Broad Institute of MIT and Harvard )
Year:  2023-2026

Study title: Molecular regulation of trafficking misfolded proteins to the lysomes

Biography
Dr. Magdalena Riedl Khursigara completed her MD and PhD at the University of Innsbruck (Austria). She spent most of her research time for her PhD at the Research Institute of the The Hospital for Sick Children in Toronto studying the role of complement activation on endothelial cells. This was followed by a 1-year postdoctoral fellowship with Prof. Grinstein at Sickkids Research Institute studying membrane architecture and glycocalyx. She then completed her Paediatrics Residency and Nephrology Fellowship at the University of Toronto.  

Her research focuses on cell biological mechanism of kidney disease. In the future she plans to expand her knowledge in cell biology and multi-omics approaches to continue to study the fundamental mechanisms of genetic kidney diseases in children.  

Lay Summary
Kidney diseases affect more than 850 million people worldwide, and yet targeted treatments that address the root causes of disease are lacking. Here we propose to study the mechanisms that lead to a kidney disease caused by a frameshift mutation in Mucin 1, known as ADTKD-MUC1 or Mucin-1 associated kidney disease (MKD). This mutation results in a misfolded protein (MUC1-fs) that is retained in intracellular vesicles, whereby it accumulates and causes progressive tubular epithelial cell damage and subsequent kidney failure. Administration of the drug BRD4780 re-routes this misfolded protein to the lysosomes, promoting their degradation. An important open challenge is to understand precisely how misfolded MUC1-fs protein traffics to the lysosomes. Previous research has shown, that trafficking within the cell often requires changes of the lipid composition of organelle/vesicle membranes. We therefore hypothesize that misfolded protein trafficking and degradation is regulated by proteins that alter the lipid composition of vesicular membranes. By doing so, they generate a specific “postal code” for vesicular trafficking to the lysosomes that allows their protein cargo to be degraded.

In Aim 1 we will study the mechanism involved in the trafficking to the lysosomes, including two promising proteins that are involved in lipid composition of vesicle membranes – STARD3 and SC5D. STARD3 is a protein that exchanges cholesterol between organelle membranes and SC5D is an enzyme involved in cholesterol biosynthesis.

In Aim 2 we will study lipid compositions of vesicles and other organelles involved in the pathway to the lysosomes. Here, we propose to take advantage of previously well-established models such as an immortalized tubular epithelial cell line from a patient with MKD, and patient derived organoids as well as a knock-in mouse model that recapitulates the human phenotype. We will investigate our aims using state-of the art imaging techniques, as well as metabolomics/lipidomics approaches (an unbiased approach to study proteins or lipids of cells or organelles). We ultimately propose to validate our findings in vivo by generating STARD3 knockout mice and crossing them to MUC1-fs knock-in mice.

Understanding in depth mechanism of diseases is very important to develop new therapies and to change lives. Patients with MKD show slowly progressive kidney disease with requiring dialysis in their 40s. With this proposal we want to stop the progression of kidney disease in patients with MKD and other kidney disease where misfolded protein accumulation is the key mechanism for disease.