CADASIL-iMATTR · Investigation of Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL) using induced pluripotent stem cell modelling and targeted therapeutic research
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2023-05-01 → 2026-06-30
- EU contribution
- €278,571
- Participants
- 3
- Scheme
- HORIZON-TMA-MSCA-PF-GF
Lines connect the coordinator with its partners.
Results in brief
Investigation of Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL) using induced pluripotent stem cell modelling and targeted therapeutic research
This project aims to understand the underlying cause of stroke and cognitive impairment. These conditions can be caused by changes in the blood vessels of the brain. Patients with a genetic condition known as CADASIL or Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy suffer from strokes and cognitive impairment. This condition is caused by a mutation in a gene called NOTCH3. This causes alterations in the blood vessels that carry nutrients to the brain. There remains much to discovered in how damage of the blood vessels occurs, how strokes occur and how cognitive impairment occurs. Currently, there are no cures or treatments available for CADASIL. There are also a lack of cell and animal models available to test potential new treatments. Our first aim is to understand as much about the disease in humans as possible through an in depth analysis of blood samples and brain samples. Secondly we aim to develop a cell model in a dish to mimic the dysfunction occurring in patients with CADASIL and to see if we can apply new and existing therapies to repair any dysfunction. Thirdly, we aim to use a specific type of fish, a Zebrafish, with fluorescent blood vessels, to see if we can establish an animal model of CADASIL for testing of therapies. We anticipate that this project will have a significant impact on the CADASIL community of patients and researchers and beyond. Outcomes from this project will not only enhance our understand of the disease in early and late stage but also form the basis of establishing pre-clinical models for testing of potential treatments for CADASIL. We would like to thank all the people who donated biospecimens to this research project.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN · DublinCoordinatorIreland
- Harvard Medical School · BostonUnited States
- ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · NEW YORKUnited States
Links
- View on CORDIS
- DOI: 10.3030/101111254
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e50ad95dde&appId=PPGMS
Data: CORDIS, © European Union