Finding safe and effective therapies for stroke in children

Cerebral cavernous malformations (CCMs) are dilated blood vessels that form a non-malignant but potentially fatal condition causing strokes. Commonly detected in the brain in as many as 1/200 individuals, CCM is a major cause of stroke in young people who therefore lose many years of quality life. Brain surgery is only available treatment, hence new CCM therapies are urgently needed.

Our research group has made major contributions to CCM research from animal models to molecular signaling to imaging technique in recent years which include identification of the key signaling pathways in CCM disease and repurposing the first FDA-approved drug to treat experimental CCM.

Project 1

Clinical observations and our preliminary data in mouse models demonstrate greater CCM burden in males. Male predisposition to CCM likely reflects the impact of sex hormones on pathology, since men have earlier onset and more severe cardiovascular disease than women. Whether the pronounced sex difference reflects a protective effect of estrogens/progesterone or a deleterious effect of androgens is unknown and has not been studied. Hence, the project aims to elucidate the roles of sex hormones in CCM and reveal the potential use of sex hormones as a CCM therapy.

Project 2

We recently identified the gut microbiome as a critical stimulant of CCM. Broad-spectrum antibiotics prevented CCM lesion formation in mouse models. Despite being highly effective in mouse models of disease, the continued use of broad-spectrum antibiotics is not suitable for long term treatment of CCM patients, as they kill bacteria that are beneficial to human health, which in turn is likely to have many side effects. Our finding has suggested novel therapeutic strategies by targeting the gut microbiome. Hence, the project aims to elucidate the roles of the gut microbiome in CCM and reveal the potential use of microbiome targeted CCM therapy.