Research Opportunities

Accumulation of misfolded proteins and aberrant protein aggregates are hallmarks of a wide range of pathologies such as neurodegenerative diseases and cancer. Under normal conditions, these potentially toxic protein species are kept at low levels due to a variety of quality control mechanisms that detect and selectively promote their degradation. Our lab investigates these protein quality control processes with a particular focus on ER-associated degradation (ERAD), that looks after membrane and secreted proteins. The ERAD pathway is evolutionarily conserved and in mammals, targets thousands of proteins influencing a wide range of cellular processes, from lipid homeostasis and stress responses to cell signaling and communication.

We investigate the mechanisms of ERAD using multidisciplinary approaches both in human and yeast cells. Using CRISPR-based genome-wide genetic screens and light microscopy experiments we identify and characterize molecular components involved in the degradation of disease-relevant toxic proteins. In parallel, we use biochemical tools to dissect mechanistically the various steps of the ERAD pathways. In this collaborative project with the Lea lab we will use structural approaches such as cryo-electron microscopy to gain insight into the molecular mechanisms of ERAD.

These studies, by providing mechanistic understanding of the ERAD process, may shed light on human diseases impacting ER function and may ultimately contribute to better therapeutics. 

Recent work in the Nitschke group has produced cages potentially capable of encapsulating proteins or nucleic acids. This project will develop the encapsulation of these biomolecules, and study their properties and potential therapeutic applications.

Creatine is an important energy storage and transfer molecule in muscle and brain but is synthesized primarily in the kidneys and liver. Hence, creatine uptake in skeletal muscle, brain, and heart is dependent on the creatine transporter (CrT or SLC6A8). Loss-of-function mutations in CrT are the second most common cause of X-linked intellectual disability and low tissue creatine levels result in skeletal muscle atrophy and are closely associated with heart failure. Cells down-regulate expression of CrT when creatine levels are high, but the mechanisms underlying this autoregulation and the importance to normal physiology and disease are unknown.

Recently, we found that creatine feedback inhibits translation of the CrT mRNA to control transporter production, and we identified elements in the CrT mRNA that are important for this control. This PhD project will involve molecular genetic analyses to more fully characterize the translational control mechanism(s) by which creatine feedback inhibits its own cellular uptake. In addition, CRISPR-Cas technology will be used to eliminate the translational control mechanisms in mice, and then physiological studies of the mice will be used to characterize the role of CrT autoregulation.

A signalling pathway linking nutrient availability to changes in gene expression that hinges on the phosphorylation of translation initiation 2 (eIF2) has long been known to exist. Recognized initially as the yeast General Control Response, recent convergent lines of research have implicated its metazoan counterpart, the Integrated Stress Response, in diverse physiological processes ranging from immunity to memory formation.

This PhD programme will exploit our emerging detailed understanding of translation initiation and termination to shed light on unanticipated mechanistic aspects of the ISR. An understanding of these details may inform efforts to target the ISR to therapeutic ends.

The goal of our research is to understand how cells use various protein quality control (PQC) strategies to eliminate misfolded proteins, and how defects in these processes lead to aging-associated neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Specifically, we study the molecular mechanisms underlying protein translocation-associated quality control at the endoplasmic reticulum (ER), the export of misfolded proteins via unconventional protein secretion, and cell-to-cell transmission of misfolded alpha-Synuclein and Tau aggregates. We envision that a thorough characterization of these protein quality control systems may one day improve both diagnosis and treatment of aging-associated neurodegenerative diseases.

The project will use X-ray crystallography, cryoEM, microbial genetics and molecular biology to explore how small RNAs and small proteins act as regulators with speed and precision in diverse bacteria.

Study of the PTM and protein expression dynamics in the Toll-like receptor pathway. Because dynamic PTMs such as phosphorylation, ubiquitination, or glycosylation are essential for the regulation of cell signaling, it is crucial to quantitatively map the PTMs of proteins involved in signaling cascades. We use the data to model the signaling network changes and their impact on innate immunity.