Using β2 agonists to treat TBI

Exploring the role of adrenergic signalling and therapeutic effects of β2-adrenergic agonists in traumatic brain injury

Degree type

PhD

Closing date

29 October 2021

Campus

Hobart

Citizenship requirement

Domestic/International Onshore

About the research project

Traumatic brain injury (TBI) is a devastating condition that constitutes a major health and socio-economic burden in Australia and world-wide. There is an urgent need for the development of neuroprotective therapies for TBI, and to date, approximately 30 clinical trials in TBI have failed. Many of these were testing neuroprotective agents targeting individual pathological processes that contribute to the ongoing neurodegeneration that occurs after injury, such as excitotoxicity, oxidative stress and inflammation. It has more recently been recognised that successful pharmacological intervention will likely require drugs that target multiple injury cascades. Thus, with this project we will explore one such class of drugs, β2-adrenoceptor (β2AR) agonists, as potential therapeutics for the treatment of TBI.

β2AR agonists are a group of drugs that are mimetics of endogenously occurring catecholamines, and have been successfully employed for decades to treat respiratory diseases such as asthma. More recently, their potential value for treating neurological disorders has been identified. Activating β2ARs on neurons, astrocytes and/or microglia in in vitro and in vivo models of neurodegeneration attenuated neuroinflammation and oxidative stress, and increased mitochondrial biogenesis and production of neurotrophic factors. Moreover, despite being relatively hydrophilic compounds, β2AR agonists are known to cross the blood-brain barrier. These multipotent actions make β2AR agonists a compelling candidate for the treatment of TBI.

β2AR agonists are chiral compounds (non-superimposable mirror image molecules) consisting of (R)- and (S)-enantiomers, and are most commonly administered as 50:50 racemic (rac-) mixtures of both enantiomers. Importantly, studies have shown that the activation of β2ARs is stereospecific, and the enantiomeric specificity can be important for agonist-induced functional responses. This aspect of stereospecificity has been only minimally explored in the context of the central nervous system, and moreover, the relative permeability of the blood-brain barrier to the different enantiomers is unknown.

Therefore, the first aim of this project is to characterise the pharmacokinetics of a range of short- and long-acting β2AR agonists in mice, with a particular focus on the enantioselectivity of blood-brain barrier permeability. Based on these results, we will select specific β2AR agonists to use in subsequent experiments testing the therapeutic efficacy of these drugs in a mouse model of TBI. The project will also explore central adrenergic signalling pathways involved with TBI.

Primary Supervisor

Meet Dr Nicole Bye

Funding

Applicants will be considered for a Research Training Program (RTP) scholarship or Tasmania Graduate Research Scholarship (TGRS) which, if successful, provides:

  • a living allowance stipend of $28,597 per annum (2021 rate, indexed annually) for 3.5 years
  • a relocation allowance of up to $2,000
  • a tuition fees offset covering the cost of tuition fees for up to four years (domestic applicants only)

If successful, international applicants will receive a University of Tasmania Fees Offset for up to four years.

As part of the application process you may indicate if you do not wish to be considered for scholarship funding.

Eligibility

The project is open to domestic (Australian and New Zealand) and international applicants who are already in Australia (onshore) at the time of submitting their application.

Due to current Australian COVID-19 travel restrictions the University cannot accept applications from international applicants who are currently overseas.

Applicants should review the Higher Degree by Research minimum entry requirements.

Selection Criteria

The project is competitively assessed and awarded.  Selection is based on academic merit and suitability to the project as determined by the College.

Application process

There is a three-step application process:

  1. Select the project, and check you meet the eligibility and selection criteria;
  2. Contact the Primary Supervisor, Dr Nicole Bye, if you have any questions about the project; and
  3. Click here to submit an application by the closing date listed above.
    • Copy and paste the title of the project from this advertisement into your application. If you don’t correctly do this your application may be rejected.
    • As part of your application you will be required to submit a covering letter, a CV including contact details of two referees and your project research proposal.

Following the application closing date applications will be assessed within the College. Applicants should expect to receive notification of the outcome by email.

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