Analia Garcia, D.M.D. is an assistant professor at the Temple University Medical School. After her postdoctoral training in the molecular mechanisms of neutrophil and platelet activation, she was recently advanced to a faculty status. As an underrepresented minority, this award mechanism, Mentored Career Development Award to Promote Faculty Diversity in Biomedical Research, would help Dr. Garcia advance her academic research career by providing mentoring, facilities, and resources. Intellectual resources at Temple University faculty, including her mentor, Satya P. Kunapuli, Ph.D and co-mentor, Raul De La Cadena, M.D., and her advisory committee, working in the fields of inflammation, arthritis, and thrombosis are a great asset for her growth. Her research project is at the cross roads of inflammation and thrombosis, as it is becoming increasingly clear that inflammation and thrombosis are closely related processes and that activated platelets might be important in the regulation of inflammation. Clopidogrel (trade name Plavix), antagonizing P2Y12 receptors on platelets, is a widely used potent anti-thrombotic agent. Clopidogrel also inhibits the release of several chemokines and nucleotides from platelet granules that activate leukocytes. However, the effect of Clopidogrel or the platelet P2Y12 receptor blockade on inflammation has not been thoroughly evaluated. In the literature there are at least three clinical cases, including a recent double blind study, where Clopidogrel treatment aggravated inflammation. We hypothesize that "activated platelets regulate lymphocyte function thereby influence the inflammatory responses". The overall goal of this proposal is to "Evaluate the role of platelet P2Y receptor subtypes and activated platelets in animal models of inflammatory diseases". Our preliminary results show that Clopidogrel treatment, that dampens platelet activation, aggravates the inflammatory responses in a PG-APS -induced arthritis in a rat model. We will use several animal models of arthritis and inflammation to evaluate the effect of Clopidogrel and prasugrel, to test the hypothesis that Clopidogrel treatment increases inflammatory responses. As the platelet P2Y12 receptor is the known target of Clopidogrel, we will test the hypothesis that the P2Y12 receptor blockade reduces inflammatory responses but Clopidogrel treatment enhances inflammatory responses through non-selective action on other bloods cells, using multiple complementary approaches including in vivo use of Cangalore, a reversible antagonist of the P2Y12 receptor and the P2Y12 null mice. We will also evaluate the function of the leukocytes to test the hypothesis that Clopidogrel, prasugrel, or the corresponding active metabolitse affect the leukocyte function. These studies will also be performed with human leukocytes using the active metabolite of Clopidogrel or prasugrel. Further, they will also help us understand the role of P2Y12 receptors in inflammation and contribute to better treatments and to design therapeutics for inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL092586-05
Application #
8268997
Study Section
Special Emphasis Panel (ZHL1-CSR-G (F1))
Program Officer
Sarkar, Rita
Project Start
2008-09-26
Project End
2013-11-30
Budget Start
2012-06-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$140,130
Indirect Cost
$10,380
Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Liverani, Elisabetta; Rico, Mario C; Garcia, Analia E et al. (2013) Prasugrel metabolites inhibit neutrophil functions. J Pharmacol Exp Ther 344:231-43
Garcia, Analia E; Rico, Mario C; Liverani, Elisabetta et al. (2013) Erosive arthritis and hepatic granuloma formation induced by peptidoglycan polysaccharide in rats is aggravated by prasugrel treatment. PLoS One 8:e69093
Garcia, Analia E; Mada, Sripal R; Rico, Mario C et al. (2011) Clopidogrel, a P2Y12 receptor antagonist, potentiates the inflammatory response in a rat model of peptidoglycan polysaccharide-induced arthritis. PLoS One 6:e26035
Garcia, Analia; Kim, Soochong; Bhavaraju, Kamala et al. (2010) Role of phosphoinositide 3-kinase beta in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways. Biochem J 429:369-77