Mitochondria: An Emerging Therapeutic Target for Neurodegenerative Diseases.

Healthy mitochondria are essential for the functioning of the brain. In neurodegenerative degenerative disease states, an accumulation of dysfunctional mitochondria is observed. This has been hypothesised as a probable cause of neurodegeneration. My project aims to develop therapeutics that activate a process that removes dysfunctional mitochondria called “mitophagy” through the use of small molecules.

Exploring Molecules that Ameliorate Social Dysfunction

I am currently working on the development of new therapeutics to manage social dysfunction and its related mental disorders. Current therapeutics such as SSRIs, SNRIs, tricyclics and MAOIs suffer from poor efficacy and severe side effects, leaving much to be improved.  My project attempts to strike at the root cause (the underlying social dysfunction) by focusing on the development of positive allosteric modulators and bitopic ligands that instil prosocial behaviour by targeting the oxytocin receptor. I also believe i could beat an orangatang in a fight.

P2X4R Antagonists and the Modulation of Microglial Function

Chronic activation of microglia has been demonstrated to both initiate and progress a variety of pathological states such as Alzheimer’s and Parkinson’s disease. Therapeutic intervention through targeting the P2X4R has demonstrated great promise in reducing the overactivation of microglia and thereby reducing excessive initiation of pro-inflammatory signalling. SAR is currently being refined to identify key pharmacophoric features required for potent and selective antagonists, and subsequently their effect on the structure and function of microglia in a pathological state. 

Investigation of novel purinergic therapeutics for the treatment of Alzheimer’s disease and amyotrophic lateral sclerosis

Alzheimer’s Disease and Amyotrophic Lateral Sclerosis are two neurodegenerative diseases that have a significant health and economic burdens. Current treatments fail to significantly treat disease progression and only alleviate minor symptoms within each disease, respectively. Therefore, there is a need for the identification and design of novel therapeutic targets. This project will explore the design of novel purinergic therapeutics at antagonising the purinergic receptors investigated using high throughput methods. Furthermore, the project will develop a disease relevant assay for screening therapeutics using induced pluripotent stem cell derived microglia and astrocytes to identify lead compounds based of rational drug design. Techniques will include fluorescence and luminescence assays as well as western blotting.

P2X7 Antagonists and Their Role in Inflammation

Chronic inflammation has been proven to play a major role in advancing the pathologies of both neurodegenerative and cardiac diseases. The P2X7 receptor plays a prolific role in the pro-inflammatory signalling cascade, making P2X7 antagonism a promising approach for the development of anti-inflammatory therapies. My project aims to elucidate key structure activity relationships of small molecule antagonists and novel pharmacophores for the P2X7 receptor.

Drug development for neurodegenerative disease is hindered by current pre-clinical animal and cellular models which do not recapitulate the genetic and pathophysiological complexity of these conditions. Using 3D bioprinting technology and induced pluripotent stem cells (iPSCs) derived from patients with amyotrophic lateral sclerosis (ALS), my project aims to develop several in vitro multicellular models of nervous system tissue. These will serve as a screening platform to identify novel drug candidates.