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PhD Studentship

A disease model to investigate vascular endothelial function for genetic stroke CADASIL

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At a glance

Completed
Award date
October 2013 - September 2016
Grant amount
£90,000
Principal investigator
Dr Tao Wang
Institute
University of Manchester

R

  • Replacement
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Application abstract

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy), caused by NOTCH3 gene mutations, is the most common type of genetic stroke and vascular dementia. It is a systemic arteriopathy with pathological changes mainly restricted to small arteries including: 1) Vascular smooth muscle cell (VSMC) degeneration; 2) Granular osmiophilic material (GOM) deposition in arterial walls; 3) Accumulation of the extracellular domain of Notch3 protein in the basal membrane of arteries; and 4) Cerebral blood flow dysregulation. It has been 15 years since NOTCH3 was found to be the causative gene for CADASIL, but the molecular mechanisms by which the mutant Notch3 results in the pathological changes of arteries are still largely unknown. Despite interesting insights into the disease pathology uncovered using transgenic mouse models and cell based studies, it is still unclear whether NOTCH3 mutations in CADASIL are gain-of-function or loss-of-function mutations. Thus, no specific and effective treatment is available.

To clarify the molecular mechanisms of CADASIL, previous efforts have been largely focused on the vascular smooth muscle cells (SMCs) due to the prominent pathological changes in this type of cell. However, impaired endothelial cell (EC) function has been repeatedly observed in arteries of both CADASIL transgenic mice and CADASIL patients. The endothelial dysfunction could be secondary to the SMC damage, which makes the study of the interaction between ECs and vascular SMCs extremely important in CADASIL.

In intact arteries, ECs and SMCs do not function independently and Notch signalling plays a vital role in communication between the two types of cells. We hypothesise that the Notch signalling circuit between ECs and SMCs is disrupted in CADASIL by the NOTCH3 mutations. The recent advance in stem cell biology has made it possible to obtain induced pluripotent stem cells (iPSCs) from somatic cells of patients and un-affected sibling controls to generate patient-specific disease cell models. We plan to use iPSCs to obtain CADASIL patient-specific endothelial cells by targeted differentiation. The endothelial cells will be characterised for their morphology, functions and interaction with CADASIL patient-specific smooth muscle cells. We also plan to generate 3D vessels which carry patient-specific SMCs and ECs for functional analysis of the vessel as a whole.

This CADASIL model will be ideal for screening therapeutic options. Findings from the project will not only benefit CADASIL patients, but also contribute to uncovering more information relating to Notch signalling in arterial function which will have a wider impact on the investigation and treatment of EC and VSMC-involved common vascular diseases such as atherosclerosis and hypertension.