Research

The Donald P. Shiley BioScience Center is the first and only multidisciplinary center in the country to focus its research efforts on the critical nexus of infection, inflammation and cardiovascular disease.

This multidisciplinary approach, combining cardiovascular, immunological, and microbial expertise is taking place in an environment that fosters innovative research.

Research Agendas

• Role of periodontal disease in atherosclerosis.
• Potential threat of nationwide exposure to Trypanosoma cruzi through imported açaí berry products.
• Development of vaccines to protect children from coxsackievirus and influenza infection that may be responsible for heart disease decades later.

Research Collaborations

• (Protecting Myocardium by Preserving Mitochondrial Integrity) —Mark Sussman, Roberta Gottlieb, Chris Glembotski, Joan Heller Brown
• (Role of Periodontitis in Development of Atherosclerosis in Young Adults) —Roberta Gottlieb, Suzanne Lindsay, Tony DeMaria, Dan Calac, Scott Kelley

Research Updates (June 2011)

Four members of the BSC submitted a Program Project grant application to study the effect of aging and metabolic syndrome on cardioprotection mediated by autophagy. The population is aging, and metabolic syndrome (a collection of conditions including hypertension, dyslipidemia, insulin resistance, and obesity) is becoming far more prevalent. These conditions make the heart more vulnerable to damage, and increase damage after myocardial infarction. The BSC investigators, led by Roberta Gottlieb, propose to study this in a multi-year, coordinated approach. Dr. Robert Mentzer, Jr. and Dr. Bruce Ito will lead studies of cardioprotection in metabolic syndrome; Dr. Phyllis Linton will address aging and inflammation; and Dr. Gottlieb will investigate mitochondrial turnover in the heart using a recently-developed transgenic model. All studies will involve proteomic characterization in collaboration with Dr. Jennifer Van Eyk, Director of the Proteomics Center at Johns Hopkins. The grant will be considered for possible funding in the Fall.

Cynthia Perry, a UCSD doctoral student who did her thesis work in Dr. Gottlieb's lab, recently defended her thesis and graduated. Her work, exploring the cardioprotective potential of a yeast quinone oxidoreductase, was published in PLoS One*. This approach offers hope for treatment of ischemic injury to heart and brain, Parkinson Disease, and inherited mitochondrial disorders (Complex I deficiency). Because PLoS One is available free online, it has been read widely and has triggered 3 new collaborations: one with a group in Australia who seek to treat complex I deficiency disorders; one with a group in Finland seeking to develop a related protein therapeutic; and a transplant surgeon who would like to use it to improve success of lung transplants. *[Perry CN, Huang C, Liu W, Magee N, Carreira RS, Gottlieb RA. Xenotransplantation of mitochondrial electron transfer enzyme, Ndi1, in myocardial reperfusion injury. PLoS One. 2011 Feb 14;6(2):e16288. PubMed PMID:21339825; PubMed Central PMCID: PMC3038860.]

Members of the Gottlieb lab have published a paper which will appear in PLoS One online on June 8*. This study reveals an important role for Parkin in the heart. Parkin is a protein that mediates elimination of damaged mitochondria, and is the gene that is mutated in some cases of Parkinson Disease. Parkin appears to be protective against ischemic stress. Contributors to the publication include Chengqun Huang, Allen Andres (who completed his PhD at SDSU and is now a postdoctoral fellow in the Gottlieb lab), Eric Ratliff (SDSU PhD), Genaro Hernandes (MBRS scholar), and Pamela Lee (in the SDSU Masters program). *[Huang C, Andres A, Ratliff RP, Hernandez G, Lee P, Gottlieb RA. Preconditioning Involves Selective Mitophagy Mediated by Parkin and p62/SQSTM1. PLoS One, in press, 2011.]

Dr. Gottlieb recently spoke at Pediatrics Grand Rounds at the M.D. Anderson Cancer Center in Houston TX, where she presented her work on late-onset heart failure after anthracycline chemotherapy. This challenging complication of cancer treatment has been difficult to study because of the lack of a suitable animal model. Dr. Gottlieb and her collaborator at UCSD, Dr. Asa Gustafsson, developed an animal model that closely resembles the situation in patients*. More recently, the Gottlieb lab has developed a treatment that is very protective in the model, and which might be beneficial if administered to patients after they have completed their course of therapy. *[Huang C, Zhang X, Ramil JM, Rikka S, Kim L, Lee Y, Gude NA, Thistlethwaite PA, Sussman MA, Gottlieb RA, Gustafsson AB. Juvenile exposure to anthracyclines impairs cardiac progenitor cell function and Vascularization resulting in greater susceptibility to stress-induced myocardial injury in adult mice. Circulation. 121:675-83, 2010.]

Related work to test the possibility that early childhood infection with Coxsackievirus might lead to heart failure is being conducted by graduate student Jon Sin, who is co-mentored by Dr. Ralph Feuer and Dr. Gottlieb. He is using the animal model developed by Gottlieb and Gustafsson and has promising results that were presented at the recent student research symposium.

Celia Ebrahimi, a graduate student in Dr. Kelly Doran's lab, studies anthrax meningitis. A collaboration with the Gottlieb lab led to the finding that autophagy plays a role in the process of bacterial invasion. The work recently appeared in the journal Infection and Immunity*. *[Ebrahimi CM, Sheen TR, Renken CW, Gottlieb RA, Doran KS. Contribution of lethal toxin and edema toxin to the pathogenesis of anthrax meningitis. Infect Immun. 2011 Apr 25. [Epub ahead of print] PubMed PMID: 21518787.]

Members of the Gottlieb, Mentzer, and Ito labs are attending heart conferences this summer. Dr. Zoltan Giricz recently presented his work at the North American regional meeting of the International Society for Heart Research, where he showed that hypercholesterolemia suppresses autophagy. In July, at the Basic Cardiovascular Sciences council meeting of the American Heart Association, Rick Sayen will report on the use of the In Vivo Imaging System, which was acquired last year through an NIH equipment grant to SDSU, for detection of autophagy in the hearts of live mice. Dr. Gottlieb presented the recent findings on Parkin in the heart at the Congress of the Israel Heart Society in Tel Aviv in May.

Dr. Gottlieb and Dr. Mentzer participated in a workshop sponsored by NHLBI--New Horizons in Cardioprotection--which was convened to establish recommendations for future cardioprotection research. The proceedings will appear in Circulation and the Journal of Cardiovascular Pharmacology and Therapeutics.