Novel enampt targeting to modulate brain and lung injury following TBI exposure

The National Heart, Lung, and Blood Institute awarded the University of Florida $159,560 on December 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to support postdoctoral research training on ENAMPT targeting to modulate brain and lung injury following traumatic brain injury exposure.

The award funds a postdoctoral fellow's research exploring the role of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in mediating traumatic brain injury (TBI)-mediated inflammation and secondary organ injury. The research addresses the observation that approximately 25 percent of TBI-exposed patients develop acute lung injury, and that mechanical ventilation exposure contributes to brain injury and cognitive loss through a bidirectional lung-brain axis mechanism. Preliminary data generated by the principal investigator indicates that TBI-exposed rodents, civilians, and warfighters exhibit increased plasma eNAMPT levels that track with TBI severity and development of acute lung injury. The research will evaluate eNAMPT/TLR4 targeting as a therapeutic approach, leveraging a humanized eNAMPT-neutralizing monoclonal antibody (ALT-100) currently in clinical testing for acute respiratory distress syndrome.

Work is performed at the University of Florida in Jupiter, Florida, with performance through June 4, 2029. The award is structured as a Project Grant, a training vehicle under the NHLBI's competitive research training program.

Abstract

A major hallmark of traumatic brain injury (TBI), a leading cause of US disability and death, is non-resolving central nervous system (CNS) inflammation that systemically impacts multiple organs including the respiratory system. Approximately 25% of TBI-exposed patients develop acute lung injury and mechanical ventilation exposure contributes to brain injury and cognitive loss via a BI-directional mechanism termed the lung-brain axis. The PI of this f-32 application is a post-doctoral fellow who seeks to extend his training in TBI pathobiology to explore the specific role of enampt (nicotinamide phosphoribosyltransferase) in mediating TBI- mediated inflammation and injury. The PI's mentor identified nampt as a ubiquitously-expressed key metabolic enzyme regulating nicotinamide/NAD metabolism. However, similar to many damage-associated molecular pattern proteins (damps), when enampt is extracellularly secreted/released by injured cells via pyroptotic and non-pyroptotic mechanisms (or TBI exposure), circulating enampt binds to TLR4 to potently initiate or amplify innate immunity-mediated inflammation. Key preliminary data generated by the PI indicates that TBI-exposed rodents, civilians and warfighters exhibit increased plasma enampt levels that tracks with TBI severity and development of acute lung injury, findings highly similar to sepsis and ards subjects. Enampt is highly druggable and a humanized enampt-neutralizing ALT-100 monoclonal antibody (MAB) is currently being tested in the puerta clinical trial in patients with moderate/severe ards. Garcia lab publications indicate that ALT- 100 MAB is highly effective in preclinical mouse, RAT and porcine models of ards and vili and in a RAT shock tube blast model of lung injury. Thus, enampt/TLR4 targeting appears to be a promising therapeutic approach to reducing TBI-induced lung and brain injury. Via two specific aims (SAS), the PI will examine enampt/TLR4 signaling as a critical driver for TBI-mediated bidirectional injury (acute lung injury and ventilator-induced brain injury) along the lung-brain axis. SA #1 will expose both nampt genetically-engineered mice, with very strong protective phenotypes in ards/vili models, and wild type C57BL6 mice receiving the ALT-100 MAB, to moderate controlled cortical impact (CCI)-induced TBI. SA #1 will detail the CCI-mediated activation of enampt/TLR4 signaling in both brain and lung tissue injuries utilizing histologic, biochemical and genomic approaches. Using nampt genetically-engineered, CCI-exposed mice. Finally, SA #2 will determine the therapeutic impact of ALT- 100 MAB in wild type C57BL6 mice exposed to combined TBI and mechanical ventilation-induced brain and lung injuries. Successful completion of these F32 aims will provide a better understanding of the role of enampt in neuro- and systemic inflammatory signaling following TBI/MV exposure and with the ensuing first-authored publications, position the PI to submit a k-series career development award to further drive his transition to independent scientist.