Research Opportunities

The metabolic repertoire of immune cells – which encompasses metabolic enzymes/pathways, the available nutrient sensors and metabolic checkpoint kinases, and the epigenetic programming of metabolic genes – directly enables and modulates specific immune functions. Capitalizing on a large cohort of patients suffering from rare genetic immunodeficiency that have been whole-genome sequenced, our goal is to delineate the genetic and molecular basis of how cellular metabolism regulates immune-function in human health and disease states. Experimental approaches will involve genomics, molecular biology, cell biology, immunology, and biochemistry with an aim to elucidating mechanisms that lead to new treatment approaches to inborn diseases of immunity.

The last decade has witnessed repeated emergence of RNA viruses with high pathogenic potential in humans including SARS-CoV-2, Zika virus, yellow fever virus and Ebola virus. The inflammatory response to infection is a major driver of pathogenesis, but the molecular mechanisms by which these viruses initiate and dysregulate inflammation are not well defined. Mitochondria are now recognized as critical regulators of the immune system and inflammation, serving as both signaling platforms and as sources of danger-associated molecular patterns (DAMPs) to initiate diverse signaling pathways. SARS-CoV-2, like other positive stranded RNA viruses, uses membranes derived from the ER for their replication factories, but also actively manipulates mitochondria, Golgi apparatus and other membrane bound organelles for replication purposes. However, it is unclear why mitochondria are hijacked during viral replication, and what the consequences of this manipulation are to inter-organelle communication and inflammation. This PhD project will use SARS-CoV-2 infection models in tissue culture and mouse models coupled to cutting-edge microscopy analysis to determine novel ways in which mitochondrial membrane remodelling and organelle contact sites are controlled, and the importance of these events as drivers of inflammation.

Neurons are specially shaped cells that have an extremely polarized structure. They contain protrusions called dendrites and a long axon extending from cell body that connect to neighbouring cells forming a neural network. Axons and dendrites retain a dynamic plasticity throughout the whole lifespan of a neuron to ensure the ability to adjust and adapt neural network connections.  The polarity and plasticity of neurons is maintained by a cytoskeleton of actin filaments and microtubules together with associated motors and other essential proteins.

This PhD project aims to elucidate the molecular organization of axons and dendrites using in situ cryo-electron tomography (cryo-ET) of primary neurons.  We will address how cytoskeletal filaments and motors drive the branching, elongation and neural network formation. To this end we form a strong collaboration between the lab of Andrew Carter at the Laboratory of Molecular Biology (LMB), Cambridge University and Mizuno Naoko at the National Heart, Lung and Blood Institute at NIH. Mizuno’s lab’s expertise is visualizing cell shape formations controlled by remodelling of cytoskeleton and the Carter lab has a long-standing interest in how trafficking is carried out by cytoskeletal motors.

Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) bridge the resolution gap between light-microscopy and conventional structural methods for gaining information on a molecular level (X-ray crystallography/NMR).  Current technical developments further facilitate in-depth analysis of cells on a molecular level that has not been possible before. The skillset obtained in this PhD project will be highly relevant to the field of newly emerging structural cell biology.

Hibernation confers extraordinary protection against various forms of stress and insults that would be life-threatening to non-hibernators. However, the mechanisms of such promising protection remain elusive, hindering potential therapeutic applications. One of the hallmarks of hibernation is metabolic regulation, exemplified by modifications in mitochondrial respiration throughout the different stages of hibernation. Nonetheless, the possible link between metabolic regulation and cellular protection is unclear.  This project aims to study the mitochondrial regulations and their roles in metabolic adaptation during hibernation, in the context of neuroprotection.