PhD Opportunity – Developing Therapeutic approaches for haemorrhagic stroke

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Research area: Mouse genetics, haemorrhagic stroke, molecular cell biology, extracellular matrix, vascular disease, collagen, endoplasmic reticulum stress

Project outline: Stroke costs UK Society ~£8 billion annually with haemorrhagic stroke accounting for 15% of adult and 50% of paediatric stroke. There are no treatment available for haemorrhagic stroke, in part due to a poor understanding of the underlying molecular cause.

Collagen IV is the major component of a type of extracellular matrix called the basement membrane that provides essential structural support to blood vessels. We and others have shown that mutations in COL4A1 or COL4A2 (encoding collagen IV proteins) cause familial and sporadic haemorrhagic, indicating these mutations may be more common than previously expected and a potential contribution to stroke in the general population (1). Our results also reveal that endoplasmic reticulum (ER)-stress due to intracellular accumulation of mutant collagen IV is associated with disease development, and that treatment of collagen IV mutant cells can reduce ER-stress (2). This provides a golden opportunity to identify the disease causing mechanisms and explore therapeutic approaches for collagen IV diseases including haemorrhagic stroke.

We have brought together a unique cohort of cell lines from patients and animal models with Col4a1 mutations to investigate the disease mechanisms of these mutations and determine how cells respond to these mutations. The identified pathways will then be modified in cell line and animal models to investigate their role in disease development and identify their potential as a therapeutic target. As FDA approved compounds are available, this will directly inform on and may identify therapeutic approaches for haemorrhagic stroke.

Project aims:

1. Exploring genetic and high throughput approaches to identify pathways that influence disease development
2. Identify the ability of small compounds to prevent the pathological effects of collagen IV mutation in cells.
3. Modification of disease development in animal models

Techniques used: State of the art imaging techniques including 3-dimensional electron microscopy, confocal microscopy and atomic force microscopy. Molecular cell biology, animal models, MRI imaging, transcriptomics.

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