The role of mTORC1-mediated regulation of protein homeostasis in heart failure with preserved ejection fraction
Description: Heart failure with preserved ejection fraction (HFpEF) is a multi-organ syndrome that represents about 50% of total heart failure (HF) cases. Although HFpEF patients have an ejection fraction comparable to healthy individuals, they exhibit typical symptoms of HF such as diastolic dysfunction, cardiac remodeling, and exercise intolerance. Lack of effective therapies for HFpEF and poor understanding of underlying mechanisms make this disorder a major challenge of cardiovascular medicine. Dysregulated proteostasis is an important pathomechanism of various diseases. Unfolded protein response (UPR) plays a critical role in maintaining proteostasis under stress and a recent study showed that UPR is inactivated in HFpEF. However, how proteostatic maintenance changes with HFpEF and whether dysregulated proteostasis promote HFpEF pathogenesis remain unknown. Proteostasis is maintained by a tight balance of protein synthesis and degradation. Mechanistic target of rapamycin complex 1 (mTORC1) controls proteostasis by promoting protein translation and suppressing autophagy. Hyperactive mTORC1 is a pathological mechanism of cardiac hypertrophy and cardiac aging, partially through creating a proteostatic challenge. Inhibition of mTORC1 protects against pressure overload-induced cardiac hypertrophy and age-related cardiac dysfunction, but the involvement of mTORC1 signaling in HFpEF is unclear. Pilot data from our lab suggest mTORC1 activation in a mouse model of HFpEF. Moreover, we found strong premises for dysregulated proteostasis in HFpEF hearts as indicated by increased bulk protein synthesis, suppressed autophagy, and upregulated ribosomal biogenesis. Based on these preliminary data, I hypothesize that hyperactivation of mTORC1 triggers proteostatic stress and promotes cardiac dysfunction during HFpEF pathogenesis, and that mTORC1 inhibition will prevent or attenuate pathological changes in HFpEF mice. Overall goals of this project are: (I) to determine how proteostasis changes during HFpEF pathogenesis, and (II) to test if mTORC1 inhibition attenuates HFpEF development and preserves proteostatic maintenance. Successful completion of this study will allow me to uncover the mechanisms underlying the dysregulation of proteostasis during the development of HFpEF. The results of this proposal will explain how mTORC1 signaling contributes to HFpEF pathogenesis and establish mTORC1 inhibition as a potential therapy for HFpEF.
Funder: American Heart Association
Amount: $143,200
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2023-01-01
End date: 2024-12-31
Investigator: Kamil Kobak (lead)
Institution: Oklahoma Medical Research Foundation
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Funded outputs count: 3
Funder award ID: 23POST1012408
OpenAlex ID: G1598985674