PROJECT DESCRIPTION: The goal of this Administrative Supplement application is to support the purchase of a multi-lane metabolic & telemetric treadmill from Columbus Instruments. This equipment is essential for determining how preoperative exercise therapy (PET) modulates anti-inflammatory trained immunity in Kupffer cells (KCs) via hepatic vagal neurotransmitter, Acetylcholine. This study is highly relevant to the parent grant (R01GM137203) entitled "Preoperative exercise therapy for surgery triggered inflammation". Liver ischemia and reperfusion (I/R) is an unavoidable consequence of major liver resection and liver transplantation that leads to significant morbidity, mortality, and costs after liver surgery. Previous strategies to protect the liver from I/R injury have typically focused on specific known injury mechanisms, often leaving other detrimental processes unaddressed. Pre/post-operative exercise facilitates recovery after major abdominal surgery. It has beneficial effects on the surgical outcome by regulating multiple mechanisms, including the quantity and function of innate immune cells to confer an anti-inflammatory environment. We have discovered that PET significantly reduced liver damage and inflammatory responses after liver I/R via metabolic reprogramming Kupffer cells with anti-inflammatory trained immunity. However, the precise mechanisms by which PET triggers metabolic changes in KCs remains unclear. Our recent preliminary data that PET increased levels of acetylcholine in the liver and blocking α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) abrogated the long-lasting protective effect of PET on liver I/R injury. Therefore, we hypothesize that PET triggers an anti- inflammatory trained immunity in KC against liver I/R injury via cholinergic anti-inflammatory pathway (CAIP). The multi-lane metabolic & telemetric treadmill is a state-of-the-art system designed for enhanced accuracy and efficiency in metabolic and physiological monitoring during small animal exercise. Our proposed vagal tone studies with metabolic treadmill will significantly expand the scope of the parent R01 award by addressing two new questions related to those already being investigated in the parent R01 award: 1) Does PET trigger trained immunity in KC to protect liver from I/R injury via hepatic vagus nerve? 2) Does PET metabolically- epigenetically reprogram KCs via a7nAChR to trigger trained immunity? In summary, the multi-lane metabolic & telemetric treadmill will significantly enhance our understanding of the effects of PET on modulating immunometabolism in hepatic immune cells against liver I/R injury and drives significant scientific advancements in the field of immunometabolism.