Heart failure with preserved ejection (HFpEF) is rapidly coming the most common form of congestive heart failure, and there are currently no effective therapies. The lack of effective therapies underscores the urgent need to identify novel therapeutic targets to treat HFpEF. A potential treatment target is abnormal ventricular filling during diastole or diastolic dysfunction due to cardiac fibrosis. While anti-fibrosis therapies have a powerful effect on diastolic dysfunction, such therapies in humans have yielded disappointing results. Our proposal offers a novel approach to this problem by focusing on the activation of pro-fibrotic signaling downstream of transforming growth factor receptor beta (TGFβ) by the stretch sensitive potassium channel TREK-1. Mice lacking TREK-1 develop exaggerated cardiac hypertrophy in response to pressure overload yet still maintain normal diastolic function. Our preliminary data suggests that this phenotype is explained by altered fibroblast activity and disruption of TGFβ signaling. The overall objective of this proposal is to investigate how TREK-1 regulates cardiac fibrosis in response to pressure overload and to allow me to develop the skills to become an independent investigator. Our central hypothesis is that the loss of TREK-1 function attenuates cardiac fibrosis through disrupted TGFβ signaling and diminished fibroblast activation. To address this hypothesis, we will 1) determine how TREK-1 effects fibroblast function and differentiation using cardiac fibroblasts isolated from TREK-1 knockout mice and by utilizing a myocardial infarction model, 2) determine how TREK-1 affects TGFβ mediated signaling by biomechanical stretch using an in vitro cellular stretch model and 3) investigate whether the loss of TREK-1 solely in fibroblasts is protective against cardiac injury using a conditional TREK-1 knockout mouse. The proposed experiments will generate insights into the development of diastolic dysfunction due to cardiac fibrosis and novel targets to treat HFpEF.
|Program type||Fellow-to-Faculty Transition Award|
|Effective start/end date||07/01/2014 → 07/22/2015|