Area of general research interest:
Lipid mediators and their role in apoptosis, inflammation, platelet function, and aging.
Current program:
- Identify novel inflammatory lipids and characterize the signaling systems they activate
- Explore transport of bilogically active phospholipids in vivo and by cultured cells.
- Define novel pathways of platelet activation, interaction with leukocytes, and the molecular basis for aspirin resistance.
Investigators:
- Gopal K. Marathe, Ph.D., Project Scientist
- Pavel Shashkin, Ph.D., Research Associate
- Lili Yang, Ph.D., Post-doctoral fellow
- G. Thomas Brown, MD/PhD Student
- Rui Chen, M.S., Principal Technologist
- Manisha Sharma, M.S., Sr. Technologist
- Mark Calabro, B.S., Technician
- Jaiwei Chen, B.S., Graduate Student
Collaborators:
- Maria Febbraio
- Roy Silverstein
- Stan Hazen
- Ariel Feldstein
- Martha Cathcart
- Ed Plow
- Keith McCrae
Brief description:
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 platelet-activating factor (PAF) is a potent inflammatory mediator that activates all inflammatory cells. We discovered a new class of phospholipids derived from the uncontrolled oxidation of phospholipids – as happens during organ transplant injury, inflammation, and atherosclerosis – that activate PAF.
We have identified oxidized phospholipids that induce the process of regulated cell death (apoptosis) through a potent disruption of mitochondrial function. Paradoxically, dysfunctional mitochondria produce pathologic reactive oxygen radicals that not only produce more oxidized phospholipids, but also initiate an inappropriate inflammatory response, as is found in stroke and cardiovascular diseases. We find mitochondria are particularly sensitive to certain oxidized phospholipids, even when presented outside the cell.
We are seeking the identity of the mammalian phospholipid importer and are investigating 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 causing a change in their phenotype that affects thrombosis and vascular disease.
Key References:
Chen J, et al. Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis. J Lipid Res. 2007; 48:2365-76.
Chen R, Yang L, McIntyre TM. Cytotoxic phospholipid oxidation products: Cell death from mitochondrial damage and the intrinsic caspase cascade. J Biol Chem 2007;282:24842-50.
Zimmerman GA, McIntyre TM. PAF, ceramide and pulmonary edema: alveolar flooding and a flood of questios. Trends Mol Med 2004; 10:245-8.
McIntyre TM, Prescott SM, Weyrich AS, Zimmerman GA. Cell-cell interactions: leukocyte-endothelial interactions. Curr Opin Hematol 2003; 10:150-8.
Marathe GK, Prescott SM, Zimmerman GA, McIntyre TM. Oxidized LDL contains inflammatory PAF-like phospholipids. Trends Cardiovasc Med 2001; 11:139-4.
Prescott SM, Zimmerman GA, Stafforini DM, McIntyre TM. Platelet-activating factor and related lipid mediators. Annu Rev Biochem. 2000; 69: 419-45.
Marathe GK, Harrison KA, Murphy RC, Prescott SM, Zimmerman GA, McIntyre TM.
Bioactive phospholipid oxidation products. Free Radic Biol Med. 2000; 28:1762-70. [PMID: 1094621]