PROJECT SUMMARY The objective of this proposal is to determine the mechanism of action of the low molecular weight protein tyrosine phosphatase (LMPTP) in cardiac fibrosis. Cardiac fibrosis is a major contributor to the pathogenesis of heart failure. In cardiac tissue, fibrosis prompts pathological changes that include dilation and hypertrophy, and ultimately leads to heart failure. There are no FDA-approved anti-fibrotic medications for heart failure; therefore, novel agents to alleviate cardiac fibrosis are a major unmet medical need in cardiology. This proposal focuses on the tyrosine phosphatase LMPTP, which is encoded by the ACP1 gene. LMPTP has been considered an inhibitor of signaling through receptor tyrosine kinases by dephosphorylation of tyrosine residues in their activation motifs. In humans, genetic polymorphisms in the ACP1 gene encoding for high LMPTP activity are known to promote myocardial hypertrophy. We previously reported that LMPTP expression is significantly upregulated in hearts of humans with end-stage heart failure. We generated the first LMPTP knockout mice and found that when subjected to blood pressure overload through transverse aortic constriction (TAC), they are protected from cardiac hypertrophy and failure, and develop substantially decreased fibrosis in the heart. We also found that inhibiting LMPTP with a small-molecule chemical inhibitor that we developed leads to reduced cardiac fibrosis, hypertrophy, and failure in TAC-treated mice. Taken together, these findings suggest a novel role for LMPTP as a promoter of cardiac fibrosis and failure. Here we propose a series of mechanistic experiments to elucidate the physiological and molecular mechanisms of action of LMPTP in fibrosis-associated heart failure. We will (Aim 1) demonstrate that LMPTP promotes cardiac fibrosis in multiple mouse models, (Aim 2) determine the cell type by which LMPTP promotes cardiac fibrosis, and (Aim 3) determine the molecular mechanism of action of LMPTP in promoting cardiac fibrosis and failure.