Research

Across the human central nervous system, 100 billion nerve cells (neurons) form complex networks to receive, integrate and analyse information and control appropriate responses. The vertebrate retina in the eye is the light sensing part of the central nervous system that initiates neural networks analysing visual information. The accessibility of this organ and the highly organised laminar arrangements of its five main types of neurons makes the retina an ideal model for understanding neural generation both during development and regeneration. Combining the retinal model with the zebrafish vertebrate model allows us to utilise genetic, technical and highly regenerative advantages to assess aspects of neurogenesis that are difficult to study in other vertebrate animals.

 

Disease modelling

We have established histological (analysis of cell morphology and tissue organisation), physiological (electroretinography to analyse neural circuit function within the retina) and psychophysics (optomoter response test to assess visual processing) techniques in the lab to establish and study novel genetic models of human diseases.

Additionally, we are using our phenotype pipeline to screen through candidate genes identified in human genome wide association studies to rapidly identify the potential contribution and effect size of individual gene candidates. We currently have projects in the lab using this approach to target gene candidates implicated in complex neurological disorders including schizophrenia and autism, as well as visual refractive disorders including childhood onset myopia.

Fate specification and subtype diversification

The major retinal neuron types can be subdivided into morphologically and functionally diverse subtypes, each involved in encoding different submodalities of vision (e.g. colour vision vs. motion detection). We are interested in identifying the genes that control this process and how their expression relates temporally within developing progenitor cells to direct the final fate choices. By combining trangenic reporter lines with live imaging techniques, we can visualise gene networks throughout the entire process of retinal development. Current projects have focused on the specification of the most diverse neurons in the retina, the amacrine interneuron, of which there are 25 – 30 subtypes in the vertebrate retina.

AC_website_figSchematics of the 28 morphologically distinct amacrine cells we identified in the zebrafish retina are shown on the left and micrographs of real cell examples on the right.

 

Neural regeneration in the adult vertebrate

While adult neural regeneration in mammals is very poor, the zebrafish regenerates neurons efficiently after a plethora of different injury or disease models to restore full function. Projects in the lab focus on understanding the mechanisms involved in this process as well as understanding why other vertebrates that could activate expression of the same genes are not able to regenerate neurons after cell loss, which occurs for example after traumatic injury or in neurodegenerative diseases.

Retinal_regenThe schematic of a cross section through zebrafish retina shows the organisation of vertebrate Muller glia cells (green), which respond to different injuries by de-differentiating into proliferative (red nuclei in the micrographs) progenitors that are able to regenerate lost neurons. Whilst humans have these same cell types, such regeneration occurs at very limited efficiency in mammals.

AVID was created in 2020 by Dr Paolin Cáceres Vélez and Dr Patricia Jusuf. This research is focused on the potential for sustainable natural resources to improve human health, identifying novel neuroprotective pathways to develop efficient therapeutic strategies, and subsequent clinical translation. Australia has a vast number of plants producing natural antioxidant compounds, which could be used to treat neurodegenerative diseases, specifically visual disorders, in which mitochondrial metabolism imbalance plays a central role by stimulating pro-regenerative / survival factors. Although interest in antioxidant compounds from Native Australian plants has increased in the last decade, the benefits of such compounds have still not been evaluated. AVID is exploring for the first time how compounds from Native Australian plants can protect neurons or modulate gene expression to ameliorate visual disorders and improve human health.

Why do we focus on oxidative stress and mitochondrial dysfunction?
A multitude of genetic and environmental factors contribute to glaucoma, many of which cause an imbalance between oxidants and antioxidants in the affected ganglion nerve cells. This oxidative stress leads to mitochondrial dysfunctions that have been implicated in several age-related neurodegenerative diseases, including glaucoma, contributing to symptoms linked to cell ageing and degeneration.
Thus, AVID explores how mitochondrial targeted therapies could provide a novel potential approach for protecting neurons or mediating specific genetic pathways to improve neural regeneration.

Which ones are AVID preclinical models?
Vertebrate organisms are powerful models for studying human disease due to their strong genetic, anatomy, physiology conservation and ease of manipulation, with the added benefit to predict human drug efficacy and safety. Thus, AVID is developing a non-invasive rapid screening platform towards clinical translation using a variety of zebrafish mutant lines; and a rat ischemia reperfusion glaucoma model. These assessments represent a critical pre-clinical step that will allow us to develop new botanical compounds into therapeutic strategies to ameliorate ophthalmic disorders and improve human health.

Where the plants are collected?
AVID is working with local farmers! Peppermint Ridge Farm has been growing and cultivating a wide range of Australian native food plants (over thirty edible species of native food plants) for over twenty years.

 

Funding Support

Australian Research Council
KM Brutton Bequest
Melbourne Neuroscience Institute Interdisciplinary Seed Funding
Faculty of Science Grant Support Scheme
Telethon Perth Children’s Hospital Research Fund
JN Peters fellowship

 

Key collaborators

A/Prof. Bang Bui, University of Melbourne
Dr. Marco Morsch, Macquarie University,
Dr. Hafiz Suleria, University of Melbourne,
Dr. Livia Carvalho, University of Western Australia
Prof. Peter Currie, Australian Regenerative Medicine Institute
Dr. Patrick Goodbourn, University of Melbourne
Dr. Jie He, Institute of Neuroscience, Shanghai
Dr. Mirana Ramialison, Australian Regenerative Medicine Institute
Dr. Fernando Rossello, Victorian Comprehensive Cancer Centre
Dr. Tamar Sztal, Monash University
Julie Weatherhead and Anthony Hooper (Peppermint Ridge Farm Pty Ltd).