Bioscience for Health Exemplar Projects

Exemplar projects led by UoN
 Project Title Project Description Dates
The role of microRNA regulation in hypoxia in gliomas  Glioblastoma (GBM) is associated with being largely hypoxic which contributes to the limited treatment options, aggressive phenotype and poor survival. Hypoxia, a lack of oxygen, is a micro-environmental condition which initiates changes within the regulation of most biological processes. Many of these processes are regulated by small sequences of non-coding DNA called microRNA (miRNA). This project experimentally tests whether hypoxia causes a change in miRNA expression in gliomas. Cell culture of established cell lines and primary patient tumour cells are pivotal as they represent the heterogeneity of these tumours found in patients. RNA extracted from these samples are then used in a miRNA microarray which shows us which miRNAs are differentially expressed in hypoxia in relation to normoxia. Following statistical analysis, qPCR will be used to validate the targets. Analysis of targets and potential downstream miRNA targets will be undertaken by microRNA or gene knock in/down, followed by functional assays such as proliferation, migration and invasion. Orthotopic brain tumour models are also available to allow in vivo analysis of any candidates at the late stages of the project. We will seek to repurpose any known inhibitors of the regulatory pathways interrogated to test as possible candidate agents for GBM therapy. 2018-2020
The role of HOX genes in breast cancer dormancy  Each year over 55,000 women are diagnosed with breast cancer in the UK, with one in eight women developing the disease in their lifetime. Although the survival rate for breast cancer is relatively high, metastasis is a common occurrence and is the primary cause of death in cancer patients. In metastasis, malignant cells leave the primary tumour, move through the body and reach a secondary niche where they may enter a dormant, slow-cycling state. These disseminated tumour cells can remain at low numbers for years or even decades, evading traditional chemotherapies, before reactivating and colonising the secondary location. The switch between this dormant and recurrent state is understudied due to the lack of suitable methods for studying dormant cells. However, it is thought that the surrounding tumour microenvironment plays a role in signalling these dormant cells to reawaken. A candidate family of genes that act within this switch are the HOX genes. These genes encode transcription factors that are master regulators of embryogenesis, instrumental in correct body patterning during development. The project hypothesis is that changes in HOX gene expression are involved in tumour dormancy and relapse and that HOX gene signatures related to these states could represent novel prognostic biomarkers and therapeutic targets for breast cancer. In this project, platforms of dormancy including induction via physical confinement, hypoxic microenvironment and nutrient deprivation, will be tested to discover and compare the gene expression signatures of HOX genes in both proliferative and dormant cancer cells, in order to explore the role of these genes in disease relapse. 2017-2021
MicroRNA regulation in the inflammatory response

The intricacies of how microRNAs (miRNAs) regulate the inflammatory response are still largely unknown. MiRNAs regulate gene expression by binding with imperfect complementarity to sites within the 3’ untranslated region (UTR) of mRNA transcripts. This facilitates the translational repression of the transcript, often by destabilisation of the transcript, resulting in its degradation. Destabilisation occurs via the shortening of the poly(A) tail, a string of adenosine residues attached to the 3’UTR, by deadenylation machinery. It has been found that some key inflammatory genes produce transcripts with initial poly(A) tail lengths that change over the course of the inflammatory response. As such, this project aims to investigate how these changing poly(A) tail lengths affect miRNA regulation. This will be achieved via the stimulation of RAW264.7 cells with lipopolysaccharide to induce an inflammatory response. Information gleaned from this project will considerably improve our understanding of miRNA regulation. Furthermore, it enhances our knowledge of the large regulatory network controlling the inflammatory response, of which correct regulation is crucial to maintaining a healthy organism.

 2018-2022

 

Exemplar projects led by NTU
 Project Title Project Description
Pharmacological re-activation of mutant TP53 in acute myeloid leukaemia and its effect on the expression of inflammatory mediators TP53-mutated human malignancies, including acute myeloid leukaemia (AML), a difficult-to-treat haematological malignancy, are characterised by chemotherapy resistance and a poor clinical outcome. However, recent studies have shown that TP53-mutated solid tumors, including lung cancer, are amenable to respond to immunotherapy with immune checkpoint blockade. Compelling new evidence suggests that the great majority of TP53 mutations in AML are associated with loss-of-function (LOF) of the mutated protein. We have generated robust preliminary data showing that TP53 mutations correlate with the expression of inflammatory molecules in the tumour microenvironment of patients with newly diagnosed AML. This project aims to understand how the pharmacological re-activation of TP53 affects the expression of inflammatory genes in AML cell lines. We will use state-of-the-art gene expression profiling and proteomics platforms, as well as molecular biology and gene editing approaches, to interrogate the immune transcriptome and proteome of AML cells bearing TP53 mutations, specifically focusing on the interplay between TP53 and STAT1, a key interferon-inducible gene. These studies have the potential to be translated into better immunotherapy approaches for patients with TP53-mutated malignancies.
Diet and Diabetes Elevated circulating glucose and fatty acid concentrations are known to trigger and exacerbate type 2 diabetes. This project involves identifying those genes whose expression becomes dysregulated during diabetes development, thereby leading to impaired function of key cells and tissues regulating glucose homeostasis. Our recent research, utilising both Affymetrix microarray and Illumina HiSeq next generation sequencing, has enabled us to identify thousands of pancreatic genes whose expression level changes following exposure to high levels of glucose and/or fatty acids. Using a combination of different state-of-the-art non-biased bioinformatic algorithms we have now identified multiple pathways and individual targets that form the basis for current and upcoming outputs and investigations.
Protective Action of Reactive Species Scavenging in Metabolic Diseases 

Mass spectrophotometry data has recently been acquired from pancreatic beta-cells, skeletal muscle, and adipocytes, detailing advanced glycation and lipidation endproduct modification of specific proteins. Crucially, the naturally occuring dipeptide, carnosine, can prevent / reverse many of these damaging modifications, indicating potential therapeutic action of this molecule. However, carnosine turns over quickly in the body, so we are currently screening and characterising a number of non- or slowly-hydrolysable analogs (that act as either carnosinase inhibitors or carnosine mimetics) which could potentially be developed as more powerful treatments for metabolic diseases including diabetes, obesity, and cancer.
 

Biotechnology and Biological Sciences Doctoral Training Programme

The University of Nottingham
University Park
Nottingham, NG7 2RD

Tel: +44 (0) 115 8466946
Email: bbdtp@nottingham.ac.uk