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Identifying signaling and gene regulatory mechanisms of pathologic cardiac remodeling and heart failure pathogenesis
- Hsu, Austin
- Advisor(s): Black, Brian
Abstract
Heart failure is a highly prevalent and costly disease, accounting for the number one source of hospitalization and healthcare expenditures in the United States. This massive unmet medical need is further underscored by the fact that there have been no new classes of heart failure therapeutics developed in the past twenty years, highlighting the urgent need for novel biological insights to pave the groundwork for drug development. The majority of existing therapies are largely targeted at cell surface neurohormonal pathways, but fail to completely alter disease progression. Interdicting downstream signaling and gene regulatory pathways may provide an alternative and complementary therapeutic strategy. My dissertation explores the roles of two family of kinases, salt-inducible kinases (SIKs) and cyclin dependent kinases (CDKs), in the setting of heart failure pathogenesis. The data generated in this body of work implicate two salt-inducible kinase isoforms, SIK1 and SIK3, as positive and negative regulators of pathologic cardiac remodeling, respectively, that can be pharmacologically targeted with small molecule inhibitors. I also uncover a role for CDK7, 12 and 13 as positive regulators of pathologic transcription and demonstrate proof-of-concept targeting of these kinases as an effective strategy for attenuating maladaptive cardiac remodeling in heart failure. Collectively, these findings advance our fundamental understanding of mechanisms that underlie the pathogenesis of heart failure and establish novel therapeutic entry points that may be exploited for the development of drugs to treat human heart failure.
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