DPAG Postdoc Appreciation Week lunch

The coronary vascular system is a dense and diverse network of arteries, veins and capillaries that provides the blood supply to the heart, and thus is essential for efficient cardiac function. Formed during embryonic development, coronary vessels contain endothelial cells (ECs) that originate from both the sinus venosus and the endocardium, processes which involve distinct signalling pathways. Whilst hypoxia is a known stimulus for the growth of new vessels, the manner in which it interacts with the different types and origins of coronary vessel formation is not well established. Further, the mechanisms underlying neovascular growth in response to injury-induced hypoxia in the adult heart remain poorly understood. Through studying gene enhancers, we identified multiple independent transcriptional pathways that regulate different aspects of coronary vessel development in the mouse. We investigated the consequences of myocardial hypoxia on these developmental pathways by combining a cardiomyocyte-specific knockdown of the Phd2 gene with enhancer:reporter lines. This found differential responses of VEGFA-MEF2, BMP4-SMAD1/5 and SOXF/RBPJ regulatory pathways to hypoxia, which were confirmed by single cell RNA sequencing. This work highlights the importance of considering coronary EC heterogeneity when attempting to modify the vasculature in the ischemic heart.

Parkinson’s is characterised by the degeneration of dopamine neurons, but the underlying molecular mechanisms remain incompletely understood. Calcium dysregulation has emerged as a central feature of the disease. In our work, we investigate how calcium homeostasis in patient-derived dopamine neurons differs from healthy controls, aiming to identify potential therapeutic targets.

Using stem cells to model dopamine neurons from people with Parkinson’s and healthy donors, we observe several hallmarks of disease, including altered calcium oscillation, loss of proteostasis, and energetic failure. Our research focuses on calcium dynamics within key cellular compartments, including the plasma membrane, lysosomes, endoplasmic reticulum, and mitochondria, with the working hypothesis that calcium dyshomeostasis is central to organelle and cell dysfunction.

We have identified distinct phenotypes in patient-derived neurons, such as reduced endoplasmic reticulum calcium content and impaired mitochondrial calcium buffering, which may contribute to neuronal vulnerability in Parkinson’s. Based on these findings, we are pursuing drug discovery efforts to restore calcium homeostasis. These efforts include both mechanism-based approaches and phenotypic drug screenings aimed at identifying compounds that correct the observed calcium dysregulation.

By targeting calcium dynamics, we hope to open new avenues for therapeutic intervention in Parkinson’s disease.