2026-09-22T13:37:12Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/117533 2023-07-11 col_2142_5131 col_2142_14781 com_2142_5130 com_2142_687 com_2142_397

McKim, Daniel B Gaskins, Rex H Wang, Bo Kukekova, Anna V 2022-12 application/pdf en text Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-12-01 The student, Jamal Hussain, accepted the attached license on 2022-09-15 at 16:03. The student, Jamal Hussain, submitted this Dissertation for approval on 2022-09-15 at 16:24. This Dissertation was approved for publication on 2022-09-19 at 19:11. DSpace SAF Submission Ingestion Package generated from Vireo submission #18495 on 2023-04-12 at 11:34:31 Mevalonate metabolites contribute to granulocyte chemotaxis, cytokine production, and sepsis mortality Hussain, Jamal 2022-09-19 Sepsis Statins Small Gtpases Isoprenoids Sepsis is a life-threatening condition caused by severe systemic inflammatory responses to infection that result in multiple organ dysfunction and failure. Statins, a class of medications used to treat hypercholesterolemia, dramatically increased sepsis survival. However, the pro-survival benefits of statins required significant patient pretreatment, and these unfavorable kinetics prevent the clinical utility of statins for treating sepsis. To overcome the poor clinical kinetic profile of statin intervention during sepsis, the pro-survival mechanisms of statins must first be understood. Mirroring clinical observations, chronic but not acute treatment with simvastatin significantly increased survival in a murine endotoxemia model. This was associated with reduced systemic granulocyte chemotaxis that occurred in a cell-intrinsic manner. In vitro modeling showed that statins abolished chemoattractant responses and that this could be reversed by restoring geranylgeranyl pyrophosphate (GGPP) but not farnesyl pyrophosphate (FPP) nor cholesterol. Treatment with prenyltransferase inhibitors showed that chemoattractant responses were dependent on geranylgeranylation. Proteomic quantification of prenylated proteins revealed several geranylgeranylated candidates that may mediate the effect of statins on chemotaxis, including small GTPases RhoA, CDC42, and Rac1 and also G-protein gamma subunits GNG12, 5, and 2. Given the kinetic problems with initiating statin treatment after sepsis onset, prenyltransferases are a promising interventional candidate for sepsis and critical inflammatory illness. Thesis eng https://hdl.handle.net/2142/117533 Copyright 2022 Jamal Hussain Ph.D. Dissertation Food Science & Human Nutrition University of Illinois at Urbana-Champaign Food Science & Human Nutrition