Project Summary/Abstract Sepsis-induced acute kidney injury is a major life-threatening condition with no effective therapy to date. The host responses to sepsis are wide-ranging, cell-type dependent, and importantly, temporally distinct. These cellular and molecular responses to sepsis can favorably or negatively affect host fitness. However, the distinction between adaptive and maladaptive responses is often not apparent a priori, and the same response may have opposite implications depending on where the patient is in the timeline of sepsis. Our current studies using a range of omics approaches have identified that altered polyamine metabolism is a prominent feature of sepsis-induced acute kidney injury. Polyamines, namely putrescine, spermidine and spermine, are involved in a multitude of fundamental biological processes such as protein synthesis and redox regulation both in host and pathogens. Our data demonstrate that modulation of polyamine metabolism can significantly influence the outcome of kidney injury in a highly complex manner, highlighting the need for better understanding the principles of polyamine metabolism in time and space during sepsis. Accordingly, in Specific Aim 1 of this proposal, we will examine the effects of modulating polyamines on kidney function across the timeline of sepsis. We will test the hypothesis that therapeutic effects of polyamine modulation are temporally distinct and have opposing effects between early and late phase sepsis. Furthermore, to enable a transition to clinical therapeutic applications, we will seek to define the stages of sepsis using a novel time-sensitive molecular fingerprint that is linked to the status of polyamine metabolism. In Specific Aim 2, we will determine the genome-wide molecular effects of polyamine modulation in the kidney with a primary focus on their impact on protein synthesis. Global mapping of polyamine-dependent translational changes could bridge our knowledge gap between large scale phenomena such as altered kidney function as investigated in Aim 1 and the molecular regulation afforded by polyamines at codon-level resolution.