Early damage of insulin-producing beta cells during human type 1 diabetes

Project code: MHS006

Department

Molecular Medicine and Pathology

Location

Auckland

Supervisor

Dr Shiva Reddy

Recent evidence suggests that the insulin-producing beta cells in the pancreas may not be mere passive victims of an autoimmune attack but may play an active role in the deleterious process.

In this project, we wish to obtain direct evidence of beta cell DNA damage, a process that may impair beta cell function and induce structural changes within the diabetes-prone beta cell. Such processes may result in beta cell death or may lead to recognition of modified beta cell components by antigen presenting cells, invoke T cell immune response and invasion of islets by various immune cells.

AIMS

Here, we will attempt to identify products of nuclear DNA damage within pancreatic sections from human type 1 diabetic cases and establish their cellular source/s.

Skills

Pancreatic pathology, dual and triple-label fluorescence immunohistochemistry, microscopy, image acquisition, confocal microscopy, cell counting and image re-construction.

Unravelling mechanisms of lymphatic vessel development

Project code: MHS020

Department

Molecular Medicine and Pathology

Location

Auckland

Supervisor

Jonathan Astin

Lymphatic vessels are a component of our vascular system with roles in tissue fluid homeostasis and in immune cell trafficking. Abnormal lymphatic vessel growth contributes to the pathogenesis of many chronic inflammatory conditions and cancer metastasis.Despite their importance, the mechanisms behind lymphatic vessel development remain relatively understudied. 

This project will use models of lymphatic vessel development in zebrafish embryos to examine mechanisms behind lymphatic vessel growth.

Skills

  1. live cell imaging
  2. zebrafish husbandry
  3. genetics
  4. transgenesis
  5. molecular biology

Beating the superbugs! Searching for new antibiotics from native New Zealand fungi

Project code: MHS029

Department

Molecular Medicine and Pathology

Location

Auckland

Supervisor

Dr Siouxsie Wiles

The discovery of the antibiotic penicillin, made by a fungus, began a golden age for medicine. Since then antibiotics have saved countless lives. Experts predict that within 10 years, antibiotic-resistant superbugs will bring about the end of modern medicine. Common infection will become untreatable and cancer chemotherapy and routine surgery will become life threateningly dangerous.

We desperately need new antibiotics, but where will they come from? New Zealand has a treasure trove of unique fungi that have not been exhaustively searched for new antibiotics. In this project, you will use bacteria that glow only when they are alive to rapidly identify fungi that are able to kill microbes, like the hospital superbug Staphylococcus aureus.

Skills

  • Basic microbiological skills, including induction into a PC2 lab environment, and the culture of fungi and bacteria 
  • Data collection and interpretation
  • Report writing

Trained immunity- a new path for vaccine development and immunotherapy

Project code: MHS054

Department

Molecular Medicine and Pathology

Location

Auckland

Supervisor

Chris Hall

In contrast to the adaptive arm of the immune system, the innate arm has traditionally been viewed as non-specific and lacking in memory. Recently, this dogma has been challenged by showing that cells of the innate immune system have the capacity to mount an enhanced immune response upon reinfection. Further understanding of this phenomenon, called ‘trained immunity’, has the potential to lead to new classes of vaccines and immunotherapies. We have established a zebrafish infection model that has revealed that innate immune cells within this vertebrate model system can also mount an enhanced bactericidal response upon reinfection. This project will involve exploiting the live imaging potential of the zebrafish system to further understand this exciting new area of immunological research.

Skills

1. Transgenics

2. Live cell imaging

3. Genetics

4. Molecular Biology

5.  Zebrafish husbandry

Towards an exercise pill: Can Nrf2 agonists improve mitochondrial function and biogenesis?

Project code: MHS099

Department

Molecular Medicine and Pathology

Location

Auckland

Supervisor

Troy Merry

Background

Exercise improves health, however many people cannot or do not exercise regularly. As such there is increasing interest in dissecting the mechanisms through which acts, with the ultimate goal of developing an 'exercise pill'. One of the most recognised adaptations that occur with endurance exercise training is an increase in skeletal muscle mitochondrial volume and function. Increased mitochondrial number and volume can prevent chronic diseases like diabetes and obesity. We have recently shown (Merry et al. 2016, Journal of Physiology) that the transcription factor Nrf2 plays a role in regulating exercise-induced increases in mitochondrial volume. This project will investigate the role of Nrf2 agonists in inducing mitochondrial biogenesis.

Aim

To determine whether Nrf2 agonists can promote mitochondrial biogenesis

Skills

Cell culture, western blot, qPCR, tissue extraction, cell viability assays, data analysis and presentation.

The role of pro-inflammatory cytokines in mediating beta cell death during human type 1 diabetes

Project code: MHS126

Department

Molecular Medicine and Pathology

Location

Auckland

Supervisor

Dr Shivba Reddy

The cytokines, interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) have been strongly implicated in effecting beta cell destruction during human type 1 diabetes. The cytokines may do so by up-regulating inducible nitric oxide synthase (iNOS), leading to toxic levels of nitric oxide (NO) within the islet cells. However, the expression of the two cytokines and iNOS have not been demonstrated  in islet cells from human cases with type 1 diabetes.

This project aims to demonstrate the  expression of  IL-1beta, IFN-gamma and iNOS in rare pancreatic sections from newly-diagnosed type 1 diabetic cases. We will develop sensitive immunohistochemical techniques to study the expression of the three molecules and determine their cellular sources.

Skills

Dual- and triple-Immunohistochemistry, microscopy, digital imaging, pancreatic pathology, confocal microscopy and basic immunology

Contribution of virulence factors to Staphylococcus aureus disease

Project code: MHS047

Department

Molecular Medicine and Pathology

Location

Auckland

Supervisor

Ries Langley

Staphylococcus aureus is a significant human bacterial pathogen responsible for a broad spectrum of diseases in New Zealand that range from minor skin infections through to life-threatening conditions such as septic shock.  We are interested in the Staphylococcal Superantigen-Like (SSL) proteins, a family of proteins that interfere with key components of the innate immune response such as complement, neutrophils, and pattern recognition receptors. In order to further understand the contributions of various SSLs to virulence we are generating gene-deletion (and the corresponding gene –complemented) strains of S. aureus, as well as plasmid-based reporters of gene expression. These will be analysed in various established in vitro and in vivo models of infections.
The goal of this project is to:
1) re-introduce SSL genes into gene-deletion strains of S. aureus and compare these ‘repaired’ strains with wild type S. aureus and the gene-deletion strains for their ability to resist phagocytosis and killing by human cells.
2) use plasmid-based fluorescent reporters under the control of ssl promoters to analyse the regulation of SSL gene expression in various models of infection.

Skills

Molecular biology skills, including PCR and cloning.
Microbiological skills, including induction into a PC2 laboratory environment, culturing, and genetic manipulation of bacteria.