Overview
Topic status: We're looking for students to study this topic.
Activation of Beta 1L-adrenoceptors (Beta ARs) in the heart occurs as a normal physiological response to enable the heart to maintain adequate haemodynamic function and perfusion pressure in organs. However continuous, excessive activation of Beta1 ARs in the context of heart failure causes a worsening of symptoms, morbidity and mortality. Therefore blockade of Beta1 ARs provides an important therapeutic strategy for the management of heart failure. Nevertheless, despite the use of Beta AR antagonists ( Beta -blockers), heart failure is still poorly controlled, characterized by poor prognosis, morbidity and mortality. Part of the reason might be that Beta1 ARs are incompletely blocked by currently available Beta -blockers. Two pharmacologically distinct 'states' of the Beta1 AR exist, 'Beta -1H AR and Beta1L AR'. Clinically used Beta -blockers are designed to block Beta1 HAR but not Beta1L AR and more 'complete' blockade of Beta1 ARs by more effective blockade of Beta1L ARs could be beneficial for the management of human heart failure. An understanding of the molecular features of the Beta1 AR that confers activation through Beta1L AR may contribute to the development of drugs that more completely block Beta1 ARs. The fifth and sixth transmembrane spanning domains of the Beta1 AR are critical for binding of Beta -blockers. We therefore propose to investigate these regions to determine their importance for Beta1L AR.
Hypothesis: The fifth and sixth transmembrane spanning domains of Beta1 AR are critical for Beta1L AR activity. Aim: To carry out mutagenesis studies to determine the importance of critical amino acids in the fifth and sixth transmembrane spanning domains for the activity of Beta1L AR. Research Plan: Molecular modeling will be carried out to indicate critical amino acids in the fifth and sixth transmembrane spanning domains of the Beta1 AR. They will be mutated and the mutant receptor expressed in Chinese Hamster Ovary Cells (CHO cells). Cyclic AMP experiments will be carried out to determine the activity of cardiostimulant Beta -blockers for increasing cyclic AMP. In other experiments, the affinities of Beta -blockers will be determined at mutant Beta1 ARs. These studies are expected to identify critical amino acids of the Beta1 AR that are responsible for Beta1L AR activity and lead to the development of new drugs for the management of human heart failure.
- Study level
- PhD
- Supervisors
- QUT
- Organisational unit
Science and Engineering Faculty
- Research area
- Contact
- Please contact the supervisor.
Dr Annalese Semmler
Associate Professor Peter Molenaar
