Biomedical Science

Development of heptamethine cyanine dye based theranostic compounds for inhibition of brain cancer cell lines


Dr Jiney Jose

Faculty of Medical and Health Sciences

Project code: MHS002

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common and most malignant of glial tumours which begins within the brain. It has a very poor prognosis with a median survival period of 12-15 months. The project aims to explore novel near infra-red emitting heptamethine cyanine dyes for inhibition of brain cancer cell lines. Heptamethine cyanine dyes (HMCDs) are reported to possess cytotoxic properties and therefore serve as an attractive scaffold for development of target specific anticancer drugs. There are also reports of some heptamethine cyanine dyes showing selectivity towards cancer cells compared to normal cells. This selectivity is attributed to several biological phenomena acting together but not limited to events such as activation of organic anion-transporting polypeptides on cancer cell membranes, hypoxic tumour microenvironment and mitochondrial membrane potential disruption in cancer cells. Synthetic modification of HMCDs could result in compounds suitable for treatment of GBM. 

The project will involve syntheses of various analogues of HMCDs aimed at targeting brain cancer cell lines in a modern synthetic chemistry laboratory. It will involve syntheses, purification and characterisation of analogues and testing them for activity in various brain cancer cell lines.

Diabetic retinopathy: clinical and histological assessment of the eye


Dr Monica Acosta

Faculty of Medical and Health Sciences

Project code: MHS003

Diabetes is a long-term condition that describes a group of metabolic diseases caused by high glucose levels. In the eye, diabetes causes damage to small blood vessels, which swell (called microaneurysms), and may leak blood or fluid (exudates). These retinal vascular changes may not cause eye sight problems immediately. However, left untreated, the underlying pathology may progress to a severe form of diabetic retinopathy (DR). A better understanding of DR early signs and the underlying pathophysiology is needed to prevent the otherwise inevitable advancement of the non-sight threatening form to severe vision loss.

The aim of this project is to evaluate the efficacy of an orally available Connexin43 hemichannel modulator in reducing clinical signs of diabetic retinopathy and its underlying pathology using a unique but true model of DR. In humans, optical coherence tomography imaging of the retina shows early signs of diabetic eyes, even when clinical retinopathy is undetectable. Changes in the OCT image have been associated with exudative macular oedema and retinal problems due to hypertension and have been seen around small blood vessel lesions. The preliminary investigations in the DR model show that changes in OCT images can  be associated with retinal problems.

Objective 1a: To evaluate the retinal inflammatory response associated with DR Our diabetic rats are hyperglycaemic (non-fasting blood glucose levels 14-20 mmol/l compared to normal rats with an average 9 mmol/l) and insulin resistant. Changes in the OCT image in diabetic animal may be due to local inflammation in the retina. This inflammatory response associated with DR has also been reported in humans. Correlation between clinical changes and activated microglial cells has already been confirmed in our unique animal model of DR. We will now assess the extent of retina inflammation with antibody markers for common inflammatory factors (TNF-α, vascular high-sensitivity C-reactive protein, interleukin-6). The antibodies will be applied in an immunohistochemical reaction using our standard protocols. Ocular tissues have already been collected in 4-6 weeks old rats. Age-matched Sprague Dawley rats with no ocular pathologies and normal glycaemia will be used for comparison. In addition to qualitative immunolabelling, the presence of cytokines (i.e. tissue factor, VEGF) will be examined using BD™ Cytometric Bead Arrays. Finally, Cx43 expression will also be evaluated in the retina of normal and diabetic animals with the immunohistological and molecular assessments providing a baseline map for the molecular markers to be assessed following Cx43 hemichannel block treatments.

Glucose lowering response to metformin and sulfonylurea therapy by OCT33 and CREBRF genotypes


Dr Rinki Murphy

Faculty of Medical and Health Sciences

Project code: MHS005

In clinical practice there is considerable variation in glycemic response to glucose lowering medications between individuals with type 2 diabetes. Understanding the contribution of biological factors such as sex, BMI and genotype in determining medication response is important to identify for the purpose of improving medication personalisation. 

Metformin is the first line choice for oral therapy for type 2 diabetes, followed by sulfonylurea therapy as second line and then usually insulin is added to achieve target glycemic control. As part of our genetics of diabetes study, we have consent from approximately 800 patients with type 2 diabetes who have had genetic testing for common genetic variation predisposing to diabetes risk, to evaluate their clinical records to determine their diabetes medication history and glucose control.

Aim: To evaluate the impact of OCT33 and CREBRF genotype on glucose lowering response to metformin, sulfonylurea, and time to insulin treatment. Method: Participant medication dispensing records and matching HbA1c values will be collected from clinical databases to evaluate the glucose lowering response 6 months after commencing metformin, sulfonylurea therapy and time before insulin was started. This data will be compared by OCT33 and CREBRF genotype and by preselected variable such as initial HbA1c, BMI and sex.

Placental extracellular vesicles, a role in the preventing cancers?


Dr Qi Chen

Faculty of Medical and Health Sciences

Project code: MHS013

There is rapidly growing interest in extracellular vesicles (EVs) and in their potential role in biology and medicine, including cancers. The human placenta, like most cells/tissues produces large numbers of EVs that are important in controlling the adaptations of the maternal immune and vascular systems to pregnancy, altering the function of recipient cells during pregnancy. In addition to this role in communication between fetus and its mother, we and others reported that placental EVs inhibited gynaecological cancer cell growth. This may seem surprising but cells from the placenta remain in the maternal body long after pregnancy ends and we wonder if EVs from these long-lasting placental cells are one of the factors that protect mothers from development of cancers. In this project, we hypothesize that placental EVs are capable of regulating cancer cell death. This project will help us to better understand if placental EVs protect against the development of cancers.

Characterising cellular responses to bone injury in the periosteum


Dr Brya Matthews

Faculty of Medical and Health Sciences

Project code: MHS014

The periosteum is the layer of tissues that surrounds bone and is the major source of bone and cartilage forming cells involved in fracture healing. There are still many aspects of fracture healing that are not well understood. We are interested in characterising responses of stem cell populations to injury in a mouse model. This may be done using in vitro assays after injury, or by histological and immunohistochemical analysis of marker distribution within the tissue.