PROJECT SUMMARY Approximately 1.6 million Americans suffer from leakage of their right atrioventricular heart valve, which is referred to as tricuspid valve (TV) regurgitation (TR). This is noteworthy as TR is not only a significant source of morbidity but also an independent predictor of mortality. Furthermore, treatment options for severe TR are suboptimal, with as many as 30% of patients developing recurrent TR within five years of surgery. TR is in most cases considered secondary to other conditions, implying that its causes are valve-extrinsic. Specifically, it is thought that right ventricular remodeling due to pulmonary hypertension, for example, causes papillary muscle (PM) displacement and annular dilation. PM displacement subsequently radially strains and immobilizes the TV leaflets via chordal tethering, while TV annular dilation circumferentially strains the leaflets. Together, PM displacement and annular dilation prohibit proper coaptation, rendering the TV regurgitant. Interestingly, studies on the left side of the heart have shown that mitral valve (MV) tissue grows and remodels in response to pathological mechanical (patho-mechanical) stimuli from left ventricular (LV) disease, e.g., due to leaflet strains following PM displacement and annular dilation. Although at first believed to be a positive adaptation to a changing mechanical environment, this maladaptation also causes the MV leaflets to thicken and become stiffer, further compromising valve function. The TV, on the other hand, is severely understudied. Therefore, it is unknown whether the TV similarly remodels in response to patho-mechanical stimuli, and if remodeling contributes to improper valve function. This finding would render TR not entirely valve-extrinisic and thus call into question current treatment strategies as well as potentially explain poor outcomes. To fill this gap in our knowledge, the proposed project aims to demonstrate TV remodeling in vivo in response to leaflet strain in an ovine disease model at the micro-scale (Aim 1) and the tissue-scale (Aim 2). The aims utilize state-of-the-art techniques in morphometric analysis, microstructural imaging, mechanical testing, and quantitative protein analysis and are based on a well-established tachycardia-induced cardiomyopathy sheep model. Our current lack of knowledge is potentially withholding better treatment strategies for TR, which could otherwise improve the currently poor outcomes of TV therapy. Thus, my ultimate goal is to inspire pharmacological strategies to modify the underlying biological events that lead to TV remodeling and optimize the tissue’s response to patho- mechanical stimuli. Such efforts are underway for the MV where Losartan is tested as a pharmacological treatment of MV regurgitation. Along with the research strategy, the fellowship training plan is organized to offer the applicant professional development toward an independent research career in a top tier institutional environment at ...