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Roberta A. Gottlieb


M.D., Johns Hopkins University School of Medicine

Director, SDSU BioScience Center
Frederick G. Henry Chair in Life Sciences
Professor, Department of Biology
Cell and Molecular Doctoral Program
Molecular Biology Master’s Program
Computational Sciences Doctoral Program
Heart Institute

619 594-8983


Gottlieb Lab Research Summary

Mechanisms of Cardioprotection

Our research is focused on developing ways to protect the heart after ischemia and reperfusion.  We use a range of approaches including cell biology, organ physiology, biochemistry and molecular biology to understand the intracellular processes that determine whether the cardiac cells will survive and repair, or undergo programmed cell death through apoptosis or necrosis.  We use the heart as our primary model organ but conduct many studies in cell lines or primary cell culture, using fluorescence microscopy to monitor intracellular processes in real-time in living cells.  We have a number of NIH-funded projects underway.

Rescue and Role of Complex I in Myocardial Ischemic Injury:  Members of the Bcl-2 family function at the mitochondrial outer membrane to regulate programmed cell death, or apoptosis.  Bax and Bak are multi-domain pro-apoptotic members of the family, but their activity is directly or indirectly regulated by proteins of the BH3-only subfamily (Bcl-2 relatives that only share homology in domain 3).  We are interested in Bid, a BH3-only protein that is proteolytically activated during ischemia/reperfusion and targets the mitochondria to initiate apoptosis.  Mitochondria can promote necrotic cell death through a second pathway involving a mysterious entity known as the Mitochondrial Permeability Transition Pore, which includes cyclophilin D and other components that are the subject of intense investigation.  We hypothesize that the electron transfer Complex I may be a part of the pore and may be regulated by Complex I.  We have developed a cell-permeable therapeutic protein that can protect the heart against ischemia/reperfusion injury, and we plan to test its usefulness in additional model systems.

Subcellular Regulation of Autophagy:  Autophagy is a cellular housekeeping process in which damaged organelles or insoluble protein aggregates are sequestered in a double membrane and routed to the lysosome for degradation.  We hypothesize that Bcl-2 family members regulate this process as well as apoptosis, and are interested in understanding how mitochondria may be selectively targeted for removal by autophagy.  We are also interested in understanding mitochondrial fission and fusion as a means to maintain high-quality mitochondria in the heart.  The role of autophagy in cardioprotection is an exciting new area of interest that is expanding rapidly.  In collaboration with Drs. Tom Cole (Chemistry) and Kim Finley (BioScience Center), we are developing novel tools to study and modulate the process of autophagy.

Mitochondria and Stem Cells in Anthracycline-Induced Heart Failure:  Anthracyclines are anti-cancer drugs that are used widely to treat childhood malignancies.  However, a number of cancer survivors develop heart failure 10-20 years later.  Because cardiomyocytes persist in the heart for decades, it has been assumed that cells sustain direct injury that results in eventual cytotoxicity.  However, in collaboration with Dr. Asa Gustafsson (BioScience Center), we now have evidence that anthracyclines cause early senescence of cardiac stem cells that are needed for life-long growth and repair, resulting in a limited ability of the heart to respond to physiologic stress.  We are exploring the possibility of stem cell therapy to prevent this tragic complication of chemotherapy.

Development of Small-Molecular Cardioprotective Agents for Treatment of Reperfusion Injury:  We are investigating novel compounds that protect the heart from ischemia/reperfusion injury, even when given after ischemia, at the time of reperfusion.  The mechanism of protection, optimization of lead compounds, and preclinical studies are underway in collaboration with Dr. Paul Wentworth (Chemistry, The Scripps Research Institute), Dr. Mark Yeager (Cell Biology, The Scripps Research Institute), and Dr. Robert Mentzer, Jr. (Cardiothoracic Surgery, Wayne State University School of Medicine).

Microbial Basis of Cardiovascular Disease

The focus of the BioScience Center is understanding role of infection and inflammation in the development of heart disease.  A number of early-stage collaborative projects are underway.

Role of Autophagy in Innate Immunity:  We are interested in understanding how inflammatory mediators and innate immunity regulate autophagy.  For instance, the bacterial cell wall lipid, lipolysaccharide (LPS) triggers production of Tumor Necrosis Factor alpha (TNF-a) which in turn triggers autophagy.  Is autophagy part of the injury process or a repair response?  How do bacteria (Porphyromonas gingivalis), viruses (Coxsackievirus), and protozoans (Trypanosoma cruzi) modify the cellular autophagy machinery to escape destruction once they have entered the cell?  Can we modify the infection or disease process by modulating autophagy?

Role of Periodontal Pathogens in the Development of Atherosclerosis:  In collaboration with investigators in Biology, Computational Science, and the Graduate School of Public Health, we are conducting a community-based investigation to determine if treating gum disease (periodontal disease) can prevent atherosclerosis.  We are using a metagenomics approach to define the oral microbiome in health and disease.  This collaboration involves Drs. Scott Kelley, John Mokili, Forest Rohwer (Biology), Suzanne Lindsey (Graduate School of Public Health), and Anthony Demaria (Chief of Cardiology, UCSD).

Coxsackieviral Infection of Cardiac Stem Cells:  An extension of the study of anthracycline cardiotoxicity is underway to test the possibility that viral infections in childhood might cause early senescence of cardiac stem cells that are needed for life-long growth and repair, resulting in a limited ability of the heart to respond to physiologic stress and eventual heart failure.  This work is being conducted in collaboration with Drs. Ralph Feuer (Biology) and Dr. Asa Gustafsson (BioScience Center).

Recent Publications

1.      Iwai-Kanai E, Yuan H, Huang C, Sayen MR, Perry-Garza CN, Kim L, Gottlieb RA.  A Method to Measure Cardiac Autophagic Flux in vivo. Autophagy 4:322-9, 2008.

2.      Jin JK, Whittaker R, Glassy MS, Barlow SM, Gottlieb RA, Glembotski CG.  Localization of phosphorylated {alpha}B-crystallin to heart mitochondria during ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 294:H337-344, 2008.

3.      Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 4:151-175, 2008.

4.      Tsukada YT, Sanna MG, Rosen H, Gottlieb RA.  S1P1-Selective Agonist SEW2871 Exacerbates Reperfusion Arrhythmias.  J Cardiovasc Pharmacol. 50:660-669, 2007.

5.      Benjamin IJ, Guo Y, Srinivasan S, Boudina S, Taylor R, Rajasekaran NS, Gottlieb RA, Wawrousek E, Abel ED, Bolli R.  CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice.  Am J Physiol Heart Circ Physiol. 293:H3201-9, 2007.

6.      Brady NR, Hamacher-Brady A, Yuan H, Gottlieb RA.  The autophagic response to nutrient deprivation in the HL-1 cardiac myocyte is modulated by Bcl-2 and sarco/endoplasmic reticulum calcium stores.  FEBS J. 274:3184-97, 2007.

7.      Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, Gottlieb RA, and Gustafsson AB.  Response to Myocardial Ischemia/Reperfusion Injury Involves Bnip3 and Autophagy.  Cell Death Differ.  14:146-57, 2007.

8.      Hamacher-Brady A, Brady NR, Gottlieb RA. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes.  J Biol Chem 281:29776-87, 2006.

9.      Hamacher-Brady A, Brady NR, Gottlieb RA, and Gustafsson AB.  Autophagy as a protective response to Bnip3-mediated apoptotic signaling in the heart (Addendum). Autophagy 2:307-9, 2006.

10.  Wall JA, Wei J, Ly M, Belmont P, Mardinale JJ, Tran D, Sun J, Chen WJ, Yu W, Oeller P, Briggs S, Gustafsson AB, Sayen MR, Gottlieb RA, and Glembotski CC. Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6.  Am J Physiol Heart Circ Physiol 291:H2462-72, 2006.

11.  Brady NR, Hamacher-Brady A, and Gottlieb RA.  Proapoptotic Bcl-2 family members and mitochondrial dysfunction during ischemia/reperfusion injury, a study employing cardiac HL-1 cells and GFP biosensors. Biochim Biophys Acta – Bioenergetics. 1757:667-78, 2006.

12.  Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, and Molkentin JD. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.  Nature, 434:658-62, 2005.

13.  Gustafsson AB, Tsai JG, Logue SE, Crow MT, Gottlieb RA.  Apoptosis repressor with caspase recruitment domain projects against cell death by interferfing with Bax activation.  J Biol Chem.  279:21233-21238, 2004.

14.  Granville DJ, Tashakkor B, Takeuchi C, Gustafsson AB, Huang C, Sayen MR, Wentworth P Jr, Yeager M, and Gottlieb RA. Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors. Proc Natl Acad Sci U S A 101:1321-6, 2004.

Ph.D. students:  Cyndi Perry (UCSD Molecular Pathology program)
Masters Students:  Wayne Liu, Sergey Gazarov, Joshua Millstone


Note: Entrez Medline entries for a particular Author name may correspond with multiple authors with the same initials. Also, the list is limited to entries stored in the Entrez Medline Database and may not accurately reflect the true number of publications