Inflammation triggered by loss of homeostasis in Neurodevelopmental Disease

Project description

Neurodevelopmental disorders are a group of diverse syndromes affecting central nervous system development, with typical features including deficits in intellectual, motor and sensory organ development, as well as behavioural inflexibility. Examples include autism spectrum disorder (autism), Rett syndrome, epilepsy, and schizophrenia. These disorders often co-occur (e.g. intellectual disability and epilepsy), suggesting shared molecular pathways. Neurodevelopmental disorders generally manifest in infancy or early childhood and are highly debilitating. They often result in lifetime dependence on family and the Australian healthcare system, costing an estimated AUD$20.42 billion p.a. Furthermore, these disorders are progressive and have an increased risk of premature mortality. Early intervention with cognitive therapy has shown to significantly improve patient outcomes, underscoring the crucial role of timely intervention in managing these disorders. However, cognitive therapy alone is unable to address underlying inborn errors in cellular processes that may drive disease. Thus, there is a severe unmet need for pharmacological interventions which ameliorate pathogenic pathways affecting neurodevelopment and central nervous system function.

One of the significant obstacles in pharmaceutical innovation has been our limited understanding of neurodevelopmental disorder aetiology. Whole genome sequencing has recently provided fresh insight into this, revealing that >40% of neurodevelopmental disorders have a monogenic cause. Identification of these genes has given us a foothold into understanding the pathogenic drivers of neurodevelopmental disease and therefore the opportunity to target these drivers for therapeutic benefit.

A notable proportion of causative mutations for neurodevelopmental disorders occur in genes that are associated with pathways responsible for maintaining cellular homeostasis and immune system regulation. Research conducted by our team (Davidson et al. Sci Immunol. 2022; Steiner et al. Nat Commun. 2022) and others has identified inflammatory pathways triggered by changes in cellular homeostasis via disruption of protein trafficking between organelles or inhibition of proteasomal degradation. This research reveals a complex network of surveillance by pattern recognition receptors over basic biological processes which, if disrupted, can trigger inflammation.

Maternal and early life infection has demonstrated the severely detrimental effect inflammation has on neurodevelopment. The presence of inflammatory cytokines such as type I interferon (IFNab) and interleukin-6 (IL-6) in the brains and blood of some neurodevelopmental disorder patients, in the absence of infection, has been reported. However, this area has not been thoroughly investigated, representing a major missed opportunity, especially considering the success of targeted anti-inflammatory therapeutics such as JAK inhibitors in managing childhood autoinflammatory diseases including those with neurological symptoms.

This project will develop a screen in induced pluripotent stem cell (iPSC) derived glia cell types to identify neurodevelopmental disorder associated genes which, when mutated, trigger inflammation. This screen will reveal novel regulators of inflammation. Furthermore, it will identify genetic mutations where anti-inflammatory therapy may have clinical benefit in neurodevelopmental disorders.

Students will learn:

• Culture of cell lines and iPSCs
• Differentiation of iPSCs into disease relevant cell types (eg neurons, microglia, astrocytes, etc)
• Exogenous expression of proteins
• CRISPR/Cas9 gene editing, including generating disease model iPSCs
• Flow cytometry
• Protein analysis (western blotting, ELISA, etc)
• RNA extraction and analysis (qPCR)