MDDM research group projects have attracted funding from a wide range of different organisations including Children with Cancer UK, Quintin Hogg Trust, Diabetes UK, UKRI, Society for Endocrinology and the Petts Memorial Fund.
Investigation of the ZFP36L1 protein as a candidate therapeutic target in osteosarcoma
Several AU-rich element (ARE) RNA binding proteins have recently emerged as crucial contributors to maintaining genome integrity, particularly in response to replication stress and DNA repair mechanisms. In this study, we investigated the effects of depleting ZFP36L1 using CRISPR/Cas9 in an osteosarcoma model treated with low doses of aphidicolin, a replication stress inducer. Our findings convincingly demonstrate that ZFP36L1 loss leads to genomic instability.
Funding body: Children with Cancer UK
Investigators:
- Dr. John Murphy
- Dr. Kalpana Surendranath
- Dr. Radhakrishnan Kanagaraj
A deep learning workflow for quantification of Micronuclei in DNA damage studies in cultured cancer cell lines
DNA damage response studies investigate cellular mechanisms involved in detecting and repairing DNA damage to maintain genome stability. In particular, the analysis of genome instability biomarkers, such as the cytokinesis block micronucleus assay, assessment of mitotic defects, and clonogenic assays to evaluate proliferation ability, often involves time-consuming manual analysis, which is subject to variation among individuals. In our research group, we are exploring the utilization of cost-effective AI-powered tools to streamline these repetitive and laborious tasks, offering computational excellence.
Funding body: Quintin Hogg Trust
Investigators:
- Dr. Kalpana Surendranath
- Dr. Radhakrishnan Kanagaraj
- Dr. John Murphy
- Dr. Anand Panchbhai, Logy.AI, Machine Learning Research Division, Indian Institute of Technology Bhilai, Raipur India.
Exploring the Role of RNA Binding Protein ZFP36L1 and its Potential Signatures in Enhanced Tumorigenesis
In breast cancer, RBPs have emerged as key regulators of post-transcriptional gene regulation, affecting mRNA processing, localization, stability, and translation. Our study focuses on the ARE-binding protein ZFP36L1, frequently mutated in breast cancers. Using a CRISPR-Cas9 approach, we generated ZFP36L1-deficient breast cancer cell lines to investigate its impact. Through functional, proteomic, and transcriptomic analyses, we observed that ZFP36L1 has diverse effects on cellular survival, drug sensitivity, migration, and metabolism. Ongoing studies are further elucidating the role of ZFP36L1 in various stages of cancer progression and exploring its potential as a biomarker for early diagnosis and prognosis of breast cancers.
Funding body: Quintin Hogg Trust
Investigators:
- Dr. John Murphy
- Dr. Kalpana Surendranath
- Dr. Radhakrishnan Kanagaraj
An Investigation of the Structure and Function of the Receptor Tyrosine Phosphatase CD148 and its Genetic Polymorphisms
CD148 is a widely expressed receptor-type protein tyrosine phosphatase (RPTP) and is known to have a key role in platelet signalling and thrombosis. The function of the large extracellular domain of this protein, where missense polymorphisms are located, is poorly understood. Our study is using a combination of approaches (protein structural studies, flow cytometry analysis of platelets, phosphatase inhibitors, CRISPR gene editing and T-TAS to gain greater insight into the structure and function of CD148.
Funding body: University of Westminster, UKRI, Petts Memorial Fund
Investigators:
- Dr. Alastair Barr
- Lina El-Badaoui
- Dr. Stipo Jurcevic
Investigating The Role of Platelet Activation in Thalassaemia Associated Hyper-coagulability
Haemolytic diseases are associated with formation of thrombosis and inflammation which contribute to organ damage, further complications and poor outcome. Thalassaemia is known to be a fatal and is one of the most common hereditary haemolytic anaemias worldwide. Our study focuses on clarifying the exact molecular mechanisms of platelet activation in thalassaemia patients which will indeed help determine an optimal therapeutic approach to prevent occurrence of thrombotic events in such conditions. The project uses an in vitro model system to study formation of neutrophil extracellular traps (NETs) and monocyte-platelet aggregates (MPA).
Funding body: University of Westminster
Investigators:
- Dr. Stipo Jurcevic
- Neha Thomas
- Dr. Alastair Barr
Role of co-chaperone molecule supporting metabolism and proteostasis
Aryl Hydrocarbon Receptor Interacting Protein (AIP) is a ubiquitously expressed, evolutionary conserved co-chaperone molecule, but the molecular functions of AIP are poorly understood. We have discovered a novel paediatric metabolic disorder with a severe clinical phenotype in which children born with homozygous loss of AIP are characterized by a failure to put on weight following birth, subsequently dying at an early age. We have discovered that Aip KO mouse embryonic fibroblasts (MEFs) and patient derived skin fibroblasts revealed an increase in ubiquitylated proteins and a shortage of amino acids indicating a defect in proteostasis within these cells. AIP was required to support the induction of starvation induced autophagy. We have a large, national and international cohort of collaborators involved in this project. We are also engaged in how AIP supports pro-inflammatory STING and NF-kB signaling, calcium homeostasis and growth factor signaling.
Funding body: Great Ormond Street Hospital Charity
Investigator: Dr. Oliver Harworth