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Thomas McIntyre Laboratory

❮Cardiovascular & Metabolic Sciences Thomas McIntyre Laboratory
  • Thomas McIntyre Laboratory
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Principal Investigator

Thomas McIntyre Headshot

Thomas McIntyre, PhD

Staff
Email: [email protected]
Location: Cleveland Clinic Main Campus

Research

We are interested in the molecular details of inflammation, the process that controls invading organims, and sometimes interacts with and responds to the molecules of normal cells. We focus on lipid mediatators, that is signaling molecules derived from insoluble fatty acids and phospholipids, that drive and control the innate immune or inflammatory system. We establish assays, purify enzymes, molecularly manipulate exression of enzmes, adhesion molecules and transcription factors and other elements that control the amount of the enzymes and receptors that make, metabolize or respond to lipid signaling molecules. This approach now leads to understanding acute kidney disease because chronic inflammatory and oxidative stresses damage kidney homeostasis, in part, through abnormal circulating lipid mediators. Lipid mediators are also essential, we find, in stimulated mitochondrial damage and cell death.


Biography


Education & Professional Highlights

Research

Research

We determine how cells respond to external stimuli and transduce these signals into functional responses. We explore the biology of the vascular system, particularly the rapid trafficking of inflammatory cells that underlie nearly all of the events leading to cardiovascular disease. The phospholipid PAF is a potent inflammatory mediator that activates all inflammatory cells, and many of the cardiovascular and renal systems. We discovered a new class of phospholipids derived from the uncontrolled oxidation of phospholipids – as happens during organ transplant injury, inflammation, chronic alcohol ingestion,and atherosclerosis— that activate the PAF receptor. Other oxidized phospholipids induce the process of regulated cell death, apoptosis, through a potent disruption of mitochondrial function. We find mitochondria are particularly sensitive to certain oxidized phospholipids, even when presented outside the cell. We identified a mammalian phospholipid importer, and investigate how mitochondrial function is compromised by phospholipid oxidation products. At least one unexpected outcome of this work is that platelets are directly affected by oxidized phospholipids in ways that change their phenotype in ways that affect thrombosis and vascular disease. We also find that renal cells and kidney function are compromised by circulating PAF and oxidized phospholipids in animals and humans during the chronic oxidative stress of alcohol ingestion. The regulated inflammatory mediator PAF and unregulated oxidized phospholipids signal in diverse pathologies.

Our Team

Our Team

Publications

Selected Publications

Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.

Zhu et al  Cell. 2016 165:111-24.

Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption. Latchoumycandane et al. Free Radic Biol Med. 2015;86:179-90.

Inflammatory PAF Receptor Signaling Initiates Hedgehog Signaling and Kidney Fibrogenesis During Ethanol Consumption. Latchoumycandane et al. PLoS One. 2015 Dec 31;10(12):e0145691.

Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis. Gupta et al Arterioscler Thromb Vasc Biol. 2015  35:2657-66 

Thymidine phosphorylase participates in platelet signaling and promotes thrombosis. Li et al. Circ Res, 2014, 115:997-1006

Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36, and inhibits thrombosis. Srikanthan et al J Thromb Haemostasis 2014, 11:1906-17

Proteasome proteolysis supports stimulated platelet function and thrombosis. Gupta et al Arterioscler Thromb Vasc Biol. 2014 34:160-8.

Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Latchoumycandane et al Free Radic Biol Med. 2014 69:403-16.

Careers

Careers

Training at Lerner Research Institute

Our education and training programs offer hands-on experience at one of the nationʼs top hospitals. Travel, publish in high impact journals and collaborate with investigators to solve real-world biomedical research questions.

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