Investigation of Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL) using induced pluripotent stem cell modelling and targeted therapeutic research

CADASIL, a rare disease of the small blood vessels, is caused by mutations in NOTCH3 and can cause cognitive decline leading to dementia. Vascular disease is the second most common cause of dementia with the burden set to increase with population aging. Insights into CADASIL will prove instrumental in understanding and treating the vascular contributions to cognitive impairment and dementia (VCID). There are no therapies for CADASIL and a lack of translational human models for identification of dysfunctional pathways/targets and screening of existing and novel therapeutics.Recent proteomic insights generated at the Elahi Lab show that leukocyte extravasation, vascular fibrosis and inflammatory processes are upregulated in CADASIL. This project will investigate the anti-inflammatory and anti-fibrotic effects of novel pro-resolving synthetic lipoxin mimetics (sLXms). The objectives are to investigate: (1) which cell types and pathways in the vasculature are affected in CADASIL through the use of patient-derived iPSC unicellular and multicellular vascular models; (2) which immune cell types are dysfunctional in CADASIL through immunophenotyping of patient leukocytes and assessment of immunovascular interactions; (3) can sLXms resolve these dysfunctional phenotypes through the use of patient derived-iPSC models and a Zebrafish model of CADASIL. I will work with Asst Prof Elahi, Mount Sinai, a leader in the field of VCID, during the global outgoing phase including a secondment to the Zhang Lab (Harvard). The effects of sLXms in vivo will be explored in the return phase at the Godson Lab at UCD.This interdisciplinary proposal will merge my immunotherapeutic skillset with expertise of my mentorship team and cutting-edge technologies across several disciplines (iPSC modelling, bioengineering and therapeutics) and will result in impactful discoveries for CADASIL while generating significant European economic development and strengthening transatlantic research networks.