Sepsis is the leading cause of death in US noncoronary intensive care units. Two pathognomonic features of sepsis are a profound defect in cellular oxygen extraction and inflammation, both of which may have a mitochondrial basis. Although septic subjects have mitochondrial defects, the molecular mechanisms underlying their injury that disrupt oxygen consumption and trigger inflammation remain unclear. The mechanistic platform of this proposal resides on our discovery of a unique molecular model of mitochondrial injury whereby a new protein, Fbxo48, potently disrupts mitochondrial function to trigger inflammation by mediating ubiquitin-driven disposal of a crucial cytoprotective, anti- inflammatory energy sensor, 5?-AMP-activated protein kinase (AMPK). By targeting the C- terminal molecular signature present in Fbxo48, we designed, synthesized, and tested a novel class of small molecule Fbxo48 antagonists which stabilize mitochondrial function and reduces inflammation in murine and human septic models. Hence, in this application we will first elucidate how bacterial pathogens deplete AMPK through Fbxo48, thereby accentuating experimental sepsis (Aim 1). We will specifically elucidate how Fbxo48 targets AMPK for its degradation using complementary in vitro and in vivo genetic models. Next we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary mitochondrial-protective and anti-inflammatory properties in septic models (Aim 2). These studies will provide a new pathobiologic model of mitochondrial injury that will serve as a platform for generating small molecule modulators that optimize cellular bioenergetics and limit inflammation in subjects with severe critical illness.

Public Health Relevance

Sepsis is a major cause of death in the US and evidence suggests that patients die from overwhelming lack of ability to use oxygen coupled with inflammation, making people prone to severe organ injury. The oxygen defect may be due to damage to energy- producing mitochondria in cells. We have discovered a new model that may explain these abnormalities in septic subjects that led us to develop a novel drug that reduces the oxygen defect and inflammation. This discovery fulfills an unmet need in this critical illness.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098174-07
Application #
9497827
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Aggarwal, Neil Raj
Project Start
2010-02-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Suber, Tomeka L; Nikolli, Ina; O'Brien, Michael E et al. (2018) FBXO17 promotes cell proliferation through activation of Akt in lung adenocarcinoma cells. Respir Res 19:206
Suber, Tomeka; Wei, Jianxin; Jacko, Anastasia M et al. (2017) SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3? in lung epithelia. J Biol Chem 292:7452-7461
Han, SeungHye; Jerome, Jacob A; Gregory, Alyssa D et al. (2017) Cigarette smoke destabilizes NLRP3 protein by promoting its ubiquitination. Respir Res 18:2
Lendermon, Elizabeth A; Coon, Tiffany A; Bednash, Joseph S et al. (2017) Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation. Respir Res 18:131
Londino, James D; Gulick, Dexter L; Lear, Travis B et al. (2017) Post-translational modification of the interferon-gamma receptor alters its stability and signaling. Biochem J 474:3543-3557
Bednash, Joseph S; Weathington, Nathaniel; Londino, James et al. (2017) Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity. Nat Commun 8:15203
Evankovich, John; Lear, Travis; Mckelvey, Alison et al. (2017) Receptor for advanced glycation end products is targeted by FBXO10 for ubiquitination and degradation. FASEB J 31:3894-3903
Zou, Chunbin; Synan, Matthew J; Li, Jin et al. (2016) LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. J Cell Sci 129:51-64
Liu, Yuan; Mallampalli, Rama K (2016) Small molecule therapeutics targeting F-box proteins in cancer. Semin Cancer Biol 36:105-19
Bednash, Joseph S; Mallampalli, Rama K (2016) Regulation of inflammasomes by ubiquitination. Cell Mol Immunol 13:722-728

Showing the most recent 10 out of 58 publications