Project Summary/Abstract Hypertension is a common chronic heart condition resulting in cardiac hypertrophy, dysfunction and heart failure. Mediator kinase, Cdk8 expression is increased in human and mouse models of heart failure and is sufficient to induce changes in gene expression networks resulting in cardiac dysfunction. The current proposal has three objectives: 1) determine the therapeutic potential of small-molecule Cdk8 inhibitors. 2) identify Cdk8 kinase substrates that are promising, novel therapeutic targets; and 3) determine how Cdk8 mediates cardiac transcriptional responses in vivo (e.g., by phosphorylating transcription factors and modifiers) using both the small-molecule Cdk8 inhibitors and Cdk8 conditional cardiac knockout mice. Our central hypothesis is that Cdk8 in cardiomyocytes regulates the transition from a steady-state to a hypertrophic gene program, driving functional remodeling and cardiac hypertrophy. Our preliminary data implicate Cdk8 and its substrates as potential therapeutic targets to reduce activation of the hypertrophic gene network, cardiac hypertrophy, and dysfunction in response to pathological hypertrophic stimuli. The central hypothesis will be tested via the following specific aims: (1) Confirm that Cdk8 controls the initial cardiac response to pro- hypertrophic stress [and in the later stage of HF decompensation]. (2) Determine the transcriptional consequences of Cdk8 expression and activity during hypertrophic stress. (3) Identify Cdk8 targets that differentially regulate the cardiac hypertrophic response. At the successful completion of the proposed research, the expected outcomes are: an understanding of the Cdk8 kinase-dependent and kinase-independent mechanisms that serve as a key nodal point in transcription to drive cardiac pathological gene expression networks and contribute to heart disease, and the identification of potential new treatment modalities for pathological cardiac hypertrophy and the subsequent disease. These results will provide a strong basis for further development of therapeutics targeting transcriptional mechanisms that initiate remodeling of gene networks in response to cardiac stressors, which is expected to have a significant impact on treating hypertensive cardiac hypertrophy by potentially reducing cardiac transcriptional remodeling. This research aligns with the NHLBI’s mission to promote the prevention and treatment of heart disease by further defining the activation of the hypertrophic gene network in models of heart disease.