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Thick filament-based mechanisms for the dynamic regulation of contraction and relaxation in the heart (360G-Wellcome-210464_Z_18_Z)

Recently it has become clear that, whilst the canonical calcium/thin filament-based pathway provides a start signal for contraction in skeletal muscle, its strength and speed are largely controlled by structural changes in the myosin-containing thick filaments. I now propose to test the hypothesis that thick filament regulation plays a similar key role in the dynamic control of contractility in heart muscle, by adapting and extending the methods I successfully applied to study thick filament-based regulation in skeletal muscle. I will use a fluorescence-based approach to characterise the structural dynamics of thin and thick filaments during activation and relaxation of isolated cardiac trabeculae and cardiac myofibrils. I will investigate the role of thick filament regulation and mechanical stress in determining the physiological rate of force generation and of relaxation in the heart, and how these rates are modulated in response to its functional requirements, including the stronger contraction observed after increased venous filling (the Frank-Starling law of the heart). The results of these studies are likely to lead to a new paradigm for the physiological control of contractility in the heart that will underpin future studies of the changes in that control in heart disease and potential therapeutic corrections.

£891,301

21 Feb 2018

Grant details
Amount Awarded 891301
Applicant Surname Fusi
Approval Committee Sir Henry Dale Fellowship Interview Committee
Award Date 2018-02-21T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Sir Henry Dale Fellowship
Internal ID 210464/Z/18/Z
Lead Applicant Dr Luca Fusi
Planned Dates: End Date 2023-08-31T00:00:00+00:00
Planned Dates: Start Date 2018-09-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
Sponsor(s) Prof Mathias Gautel
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