ABSTRACT Sepsis is the body's overwhelming immune response to infection that leads to organ failure and death. Refractory hypotension despite administration of vasopressors and fluid resuscitation is the most severe consequence of sepsis with a ~50% in-hospital mortality rate. Currently, there are no targeted therapies to treat sepsis. Existing treatment guidelines focus on source control and supportive care, including early administration of antibiotics and fluid resuscitation. Thus, novel genes and pathways that are involved in the pathophysiology of sepsis are actively sought with the goal to identify new targets that may offer novel therapeutic approaches. Cardiac dysfunction and hypotension in sepsis are associated with poor prognosis and increased mortality. Elevated circulating levels of B-type natriuretic peptide (BNP) correlate with myocardial stress in sepsis, as well as in other types of heart failure. Our data identified a signaling pathway that increases BNP production, which leads to lower cardiac output. We have shown that activation of cJun N- terminal kinase (JNK) contributes in the pathophysiology of sepsis. Our previous studies and new data show that cardiac JNK activation, which we have shown to be involved in sepsis pathophysiology, increases BNP expression in septic miceI. Our new data show that JNK inhibition increases blood pressure and tissue perfusion in septic mice and this is associated with lower plasma BNP levels. Thus, our central hypothesis is that activation of cardiomyocyte JNK and cJun mediates BNP upregulation in sepsis, and that inhibition of circulating BNP will alleviate septic hypotension and improve survival. To address our hypothesis we have designed the following specific aims: Aim 1 - To investigate the mechanism(s) that mediate plasma BNP increase in sepsis. Aim 2 - To assess the role of BNP in reducing CO and promoting hypotension in septic mice and patients. In summary, our goal is to elucidate the role of BNP in the pathophysiology of septic hypotension and explore the therapeutic potential of treatment strategies aimed at regulating BNP expression or neutralizing circulating BNP. Simultaneously, we will pursue clinical studies to evaluate the translational impact of our findings. Thus, we anticipate our findings to constitute the basis for designing future clinical applications aiming to alleviate septic hypotension and organ hypo-perfusion.