B11: Non-coding RNAs regulating cardiac innervation

Heart-innervating sympathetic neurons tightly control and modulate cardiac function and are primarily located in the stellate and superior cervical ganglia (SCG). These ganglia are confined, multicellular clusters of neurons, glial cells (GCs) and macrophages (MPs) among other cells. We have previously shown that innervation by the SCG determines cardiac inflammation and remodelling after myocardial infarction. In preliminary work, we found extensive pathological remodelling of the SCG itself, characterised by fibrosis and pathologically altered neurons, which are enveloped by GCs and activated MPs. Given that both, GCs and MPs, can directly influence nerve function and signalling, we hypothesise that local, intraganglionic manipulation of these neuronal microenvironment-controlling cells would be a safer and more efficient approach than targeting the relatively sensitive and inaccessible neurons themselves. Indeed, depletion of MPs from the SCG through intraganglionic injection of clodronate not only prevented neuronal cell loss and fibrosis in the SCG in a murine heart failure model, but also partially prevented cardiac dysfunction. Using state-of-the-art imaging and transcriptomics, we identified microR-21 and several MP- or GCspecific long non-coding RNAs as promising targets for intraganglionic treatment of pathological ganglionic remodelling. In this project, we aim to assess the efficacy of therapeutic targeting of these non-coding RNAs and their regulatory mechanism in the MPs and GCs of the SCG. The project will bring together and capitalize on 1) our expertise on regulatory RNA control of MP activation, including the development of a MP-targeting antisense modality, 2) our unrivalled expertise regarding characterisation and therapeutic targeting of heart disease-associated ganglionic dysfunction, and 3) our newly established methodology for the visualisation, isolation and characterisation of the GCs that envelop cardiac innervating neurons. The overall goal is to characterise candidate regulatory RNAs in ganglionic MPs and GCs for future ganglion-targeted, localized therapeutic intervention.