Dr Alessandra Granata

Alex has been a Senior Research Associate in the Stroke Research group since 2016. Her primary research focus is to develop novel treatments for vascular dementia and stroke, both of which pose significant socio-economic burdens worldwide. The approach involves utilising human stem cell-based models derived from patients affected by these diseases.

A pivotal aspect of the research involved the development of an innovative 'disease in a dish' models for the familial types of small vessel diseases (SVD), a major contributor to vascular dementia. One type of familial SVD is caused by mutations in the COL4A gene, responsible for encoding collagen IV, a crucial component of blood vessel extracellular matrix. In our model, She successfully replicated leaky small blood vessels observed in patients.

Moreover, the investigations have demonstrated the potential reversal of this leakiness through the application of inhibitors targeting matrix metalloproteinases (MMPs) in our lab disease models. This breakthrough opens doors to the development of promising new treatments targeting MMPs in vascular dementia.

Research

I lead the research group for modelling cerebrovascular diseases using patient-derived induced pluripotent stem cells (iPSC). I am based at the Clifford Allbutt Building, Central Biomedical Campus, Addenbrooke’s Site and am part of the Stroke Research Group of Professor Hugh Markus, in the department of Clinical Neurosciences.

My main research interest is to develop iPSC-based model system for genetic forms of cerebral small vessel diseases (SVD), exploiting findings from genome wide association studies (GWAS) and whole genome sequencing studies in ischaemic stroke. We believe that iPSC-derived models can be used to uncover disease mechanisms and to identify new treatments for SVD.

Publications

Key publications:

Maha Al-Thani, Mary Goodwin-Trotman…and Alessandra Granata. A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases. Stem Cell Reports, 2023, ISSN 2213-6711. https://doi.org/10.1016/j.stemcr.2023.10.014.
Granata, A. Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants. BMC Cardiovasc Disord 23, 223 (2023). https://doi.org/10.1186/s12872-023-03227-6
Davaapil H, McNamara M, Granata A, Macrae RGC, Hirano M, Fitzek M, Aragon-Martin JA, Child A, Smith DM, Sinha S. A phenotypic screen of Marfan syndrome iPSC-derived vascular smooth muscle cells uncovers GSK3β as a new target. Stem Cell Reports. 2023 Feb 14;18(2):555-569. doi: 10.1016/j.stemcr.2022.12.014. Epub 2023 Jan 19. PMID: 36669494; PMCID: PMC9968988.
Goodwin-Trotman M, Patel K, Granata A. An hiPSC-Derived In Vitro Model of the Blood-Brain Barrier. Methods Mol Biol. 2022; 2492:103-116. doi: 10.1007/978-1-0716-2289-6_5.
Granata A, Kasioulis I, Serrano F, Cooper JD, Traylor M, Sinha S and Markus HS. (2022) The HDAC9 stroke-risk variant promotes apoptosis and inflammation in a human iPSC-derived vascular model. Front. Cardiovasc. Med., 30 March 2022; https://doi.org/10.3389/fcvm.2022.849664
Pokhilko A, Brezzo G, Heilig R, Lennon R, Smith C, Allan SM, Granata A…. Horsburgh K. Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease. J Cereb Blood Flow Metab. 2021;41:2423–38.
Granata A, Serrano F, Bernard WG, McNamara M, Low L, Sastry P and Sinha S. (2017) An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nat Genet. Jan;49 (1):97-109.