Lachlan Jolly

Dr Lachlan Jolly

Research Fellow, ARC DECRA Fellow

Adelaide Medical School

Faculty of Health and Medical Sciences

Eligible to supervise Masters and PhD - email supervisor to discuss availability.


Patients with genetic conditions constitute a considerable portion of the world population with special health care needs. Our lab interrogates the 'cellular degradation pathways' with a goal of manipulating their functions to improve outcomes of such disorders, with a particular focus on neurodevelopmental disorders (NDDs).  NDDs include intellectual disability, communication disorders, autism spectrum disorder, among others, and arise during childhood. They affect ~2% of Australia’s population. In developed countries, genetic mutation is the common cause, and often not preventable (e.g. de-novo mutation). 

mRNA and protein degradation pathways display the ability to control the expression of mutant alleles, or alter the expression of homologous wildtype alleles. Manipulation of these pathways thus show great potential to alter the outcomes of genetic mutation in different contexts. We investigate how mRNA and protein ‘degradation pathways’ function to control expression of mutant and wildtype alleles involved in NDDs and other diseases. Our investigations of these pathways is providing an opportunity for the rapid derivation of new strategies to treat NDDs of diverse genetic origin. 

Our lab employs multidisciplinary and collaborative approaches. We perform functional genomic studies using cell and developmental biology techniques, utilising a variety of patient derived materials, cell, stem-cell and neural cell culture models and small animal models to interrogate the roles of cellular degradation pathways in disease pathogenesis. Our ultimate goal is to translate our discoveries into improved quality of life for affected individuals.

Major projects.

mRNA Degradation: Nonsense Mediated mRNA Decay (NMD).  NMD is an extremely important pathway because it degrades subsets of normal mRNAs, and mRNAs with premature termination codons encoded by genes with nonsense mutations = 12% of all genetic diseases. As a major modifier of disease outcomes, interrogating NMD function unlocks approaches to therapies for many neurodevelopmental disorders and genetic disease generally. We investigate how NMD controls normal mRNAs important for the function of cells of the brain, and are using our knowledge to devise new methods to both measure and manipulate NMD for therapeutic benefit. Inhibiting NMD is beneficial in contexts where haploinsufficiency causes disease, and the mutant PTC allele produces truncated proteins with all or residual function. In opposite, activation of NMD is beneficial in contexts where degradation of mutant PTC alleles is inefficient, leading to production of truncated proteins with dominant negative function.

Protein Degradation: Ubiquitin Systems We are discovering how large network of proteins encoded by neurodevelopmental disorder genes are regulated by protein ubiquitylation through studies of a network hub gene called USP9X which encodes a deubiquitylating enzyme. This is highlights opportunities to manipulate the ubiquitin-proteasome system as a therapeutic approach in neurodevelopmental disorders caused by haploinsufficiency, which can be overcome by promoting stabilisation of proteins produced from the functional wild-type alleles.

 

Successful applications I have been involved in have received in total $1.8 million dollars. This includes (Category1) $378K as ARC DECRA , $764K as CIB on NHMRC Project Grant, $238K as CIC on ARC Discovery Grant; and (Category II) $325K as CIA across 5x NFP Grants.

  1. (2010) Chief Investigator A. Women’s and Children’s Hospital Foundation Grant. $50 K. Title “Modelling the molecular pathogenesis of intellectual disability: Functional importance of the nonsense mediated mRNA decay (NMD) factor UPF3B”.
  2. (2011) Chief Investigator A. Women’s and Children’s Hospital Foundation Grant. $50 K. Title “Investigating the cell and molecular neurobiology of Usp9x: resolving the pathological mechanisms behind the genetic causes of intellectual disability”.
  3. (2013) Chief Investigator A. Women’s and Children’s Hospital Foundation Grant. $75K. Title “Molecular pathology of HCFC1, a novel modifier of embryonic neural cell behaviour involved in intellectual disability”.
  4. (2014) Chief Investigator A. Women’s and Children’s Hospital Foundation Grant. $75 K. Title “Rescue of intellectual disability severity through modification of the non-sense mediated mRNA decay factor UPF3A”.           
  5. (2014) Chief Investigator B. NH&MRC Project Grant: 1063808. $764 K. Title “The role of UPF3B and nonsense mediated mRNA decay surveillance in the pathology of intellectual disability”.
  6. (2015) Chief Investigator A. Channel 7 Children’s Foundation Grant. $75 K. Title “Visualising Nonsense Mediated mRNA Decay”.
  7. (2015) Chief Investigator B. RRI Innovation Seed Funding Program. $30 K. Title “CRISP-up: a novel Crispr/Cas9 based approach to gene overexpression”.
  8. (2016) Chief Investigator A. RRI Innovation Seed Funding Program. $25 K. Title “Generation of Pluripotent Stem Models for the study of Human Neurodevelopmental Disorders”.
  9. (2016) Chief Investigator C. RRI Innovation Seed Funding Program. $25 K. Title “The impact of Zika virus infection on placenta and neural development during early gestation”.
  10. (2017) Chief Investigator C. ARC Discovery Grant: DP170103090. $234 K. Title “TREX-mediated mRNA export: critical pathways in differentiation and function”.
  11. (2017) Co-PI. Penn Medicine Orphan Disease Centre. $70K. Titled “Understanding neurogenesis in MPS IIIA disease”.
  12. (2017) Chief Investigator C. SAFRI Simons Autism Funds. $100K. Title “USP9X in Autism”
  13. (2018) Chief Investigator A. RRI Invest for Success Funding Program. 20K. Title “Control of postnatal hippocampal development by intellectual disability genes”.
  14. (2019) Chief Investigator A. RRI Invest for Success Funding Program. 30K. Title “Control of postnatal hippocampal development by intellectual disability genes”.

Fellowships

  1. (2016-2018) ARC Discovery Early Career Research Award (DECRA): DE160100620. $378 K. Title “Seeing through the nonsense: Gene regulation and the nonsense mediated mRNA decay pathway”.
  2. (2020) Robinson Research Institute Career Development Fellowship. $100K. Title “Cellular Degradation Pathways In Neurodevelopmental Disorders”

HDR Students

  1. (2012-18). PhD. Dr Claire Homan, University of Adelaide.
  2. (2016-18). PhD. Dr Rebecca Lehmann, University of Adelaide.
  3. (2014). Undergraduate placement. Ms Deepti Domingo, University of Adelaide.
  4. (2013-current). PhD. Ms Debrah Renders, University of Adelaide.
  5. (2015-current). PhD. Ms Deepti Domingo, University of Adelaide.

Undergraduate Lectures

  1. (2016-current) University of Adelaide: Biomedical Science II, Adelaide, Australia
  2. (2018-current) University of Adelaide: Cellular Neuroscience III, Adelaide, Australia
  • Position: Research Fellow, ARC DECRA Fellow
  • Phone: 81616363, 83132454
  • Email: lachlan.jolly@adelaide.edu.au
  • Campus: Womens & Childrens Hospital, North Terrace
  • Building: WCH - Clarence Rieger Building, floor 2,Adelaide Health and Medical Sciences, floor 8
  • Room: WS8071.18
  • Org Unit: Women's and Children's Health

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