Heart failure (HF) is a devastating disease. Debilitation, mortality, and concomitant economic burden associated with HF all point to the need for new therapies to address this problem more effectively. Increased pro-inflammatory cytokines (PICs) in periphery and the central nervous system, particularly tumor necrosis factor-α (TNF-α), have been implicated in the pathophysiology of HF. However, anti-TNF clinical trials targeting peripheral manifestations of HF have failed to exhibit beneficial significance, indicating that the mechanisms of TNF-α have not been challenged. Our previous study discovered that TNF-α increases in cardiovascular/autonomic-related regions of the brain in a rat model of HF and contribute significantly to sympathetic excitation in that setting. More recently, our preliminary data indicated that TACE, a TNF-α converting enzyme, is upregulated in the paraventricular nucleus (PVN) of hypothalamus and subfornical organ (SFO) of the brain, and can alter cardiovascular function and sympathetic drive in HF rats. Unlike other cytokines, TNF-α is initially produced as a transmembrane protein (tmTNF-α). TACE is responsible for the cleavage of tmTNF-α to release its mature form, the soluble TNF-α (sTNF-α), to mediate inflammatory and immune responses. Further evidence indicated that sTNF-α binds predominantly to the TNF receptor 1 (TNFR1) to elicit pro-inflammatory and toxic responses and that tmTNF-α binds preferentially to the TNF receptor 2 (TNFR2) to display an anti-inflammatory and protective role. This project will underline the role of the brain TACE in TNF-α–induced inflammatory mechanisms driving the neurohumoral activation in HF. Using a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, and biochemistry in sham-operated and HF rats, this project will determine 1) whether TACE regulates the balance between sTNF-α and tmTNF-α in SFO and PVN in HF, and what cell types are involved; 2) whether increased TACE activity and/or decreased TNFR2 expression in brain contribute to the neurohumoral excitation in HF; 3) whether inhibition of TACE or activation of TNFR2 in the brain has a beneficial effect on cardiac function and survival rate in HF. These studies will characterize a previously unrecognized role of brain TACE in neurohumoral activation in HF and will identify a novel anti-TNF target for pharmacological intervention of HF. Completion of this research project will provide important insights into the anti-cytokine therapeutic strategy in HF and may also have implications in other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.