Adult cardiovascular disease is the most common cause of death in the industrialized world. In the United States, cardiovascular disease affects 1 in 3 adults and causes a death every 39 seconds on average. Many people associate one of the beginnings of cardiovascular disease with free radicals, which are by-products of our cells converting oxygen into energy. What we’re finding is that while free radicals may have some negative effects, such as causing damage to DNA and proteins, they are also necessary for normal functioning of the heart.
In my lab, we use the fruit fly, Drosophila, to study new mechanisms and therapeutic approaches for cardiac diseases. The fly serves as a useful model for cardiac diseases as it is the only invertebrate model system with a pumping heart that is similar to the vertebrate heart in terms of its formation and function, but is much less complex.
Both the fly and vertebrate hearts have two types of cells that “talk” to each other. Such interactions are essential for proper functioning of the heart, and the disruption of which leads to cardiac dysfunction and disease.
We hope to identify the genes and pathways necessary for the cross-talk between heart cells in flies, in particular, how free radicals could be involved in mediating the interactions. This could provide insights into human heart function and aid in the development of therapies for cardiac diseases.
B.S. Microbiology, National University of Singapore, Singapore, 1998
M.A. Pathobiology, Columbia University, New York, NY, 2001
M.Ph. Pathobiology Columbia University, New York, NY, 2004
Ph.D. Pathobiology, Columbia University, New York, NY, 2006
Honors & Awards
1996-1997 Dean’s List, National University of Singapore
1997-1998 Runme Shaw Book Prize and University medal, National University of Singapore
1998-1999 Ishihara Sangyo Kaisha Incorporation- Economic Board of Singapore Scholarship (One-year clinical training award in Osaka University, Japan)
1999-2000 Junior Research Fellowship, Institute of Molecular and Cell Biology,
2000-2001 Pre-Doctoral GRA Fellowship, Columbia University, New York
2007 A*STAR (Agency for Science, Technology & Research) Biomedical Sciences Young Investigatorship, Singapore
2008-2010 American Heart Association (AHA) Postdoctoral Fellowship
2010-2011 American Heart Association Postdoctoral Fellowship
American Heart Association
American Stroke Association
Genetics Society of America
Joined OMRF Scientific Staff in 2011
The overarching goal of my research is to uncover novel functions of genes and signaling pathways in cardiac health and disease using the adult Drosophila heart as a model system. Two directions currently being pursued are: (1) to understand how pericardial/epicardial cells influence cardiac development and function; and (2) to understand the significance of membrane phospholipid homeostasis in lipopotoxic cardiomyopathy.
The fly pericardium and its mammalian counterpart epicardium significantly regulate myocardial development and function. However, how this is achieved is not well known. Serendipitously, I have identified a novel reactive oxygen species (ROS) signaling cascade in the pericardial cells that appears to critically regulate myocardial development and function, in a non-cell autonomous fashion, via the stress-activated protein kinases (SAPK) p38 and JNK pathways. While excessive amounts of ROS are known to exert deleterious effects on organ function, physiological levels of pericardial ROS unexpectedly appear to play an essential role in myocardial growth and function. Our identification of the essential, non-cell autonomous role of pericardial ROS signaling in myocardial development and function not only helps understand cross-talk mechanisms between peri/epicardium and myocardium but also provides new insight into the emerging role of physiological ROS signaling. My future goal is directed at how this pericardial ROS signaling regulates myocardial development and function, including identifying downstream target genes or signals that mediate the effects of ROS-SAPK signaling in the pericardial cells, as well as signaling pathways that transduce the pericardial ROS-derived signals in the myocardial cells.
My other research goal centers on the elucidation of the relationship between dysregulation of phospholipid homeostasis and lipid-induced cardiomyopathy. While elevated lipid levels due to excess intake is known to cause lipotoxic cardiomyopathy, my work in flies indicates that membrane phospholipid dysregulation could serve as an alternative pathway in the pathogenesis of lipotoxic cardiomyopathy. A loss-of-function mutation in a gene, which is responsible for the synthesis of membrane phosphoethanolamine, was uncovered to cause cardiomyopathy, in a genetic screen. I further showed that the sterol regulatory element binding protein (SREBP) pathway is aberrantly activated in the mutant flies, as a compensatory hyperactive response to deficient phospholipid levels, resulting in uncontrolled lipogenesis and cardiac steatosis that culminates in the development of lipotoxic cardiomyopathy, thus establishing a molecular link between phospholipid metabolism and lipid-related heart function. I plan to employ this novel fly model of lipotoxic cardiomyopathy to genetically screen for molecular components in the cardiac lipotoxic response to dysregulated phospholipid metabolism, which could provide better understanding of the etiology of lipotoxic heart diseases. I also intend to utilize the powerful genetics of Drosophila to identify key players in lipotoxicity- and glucotoxicity-induced cardiomyopathies in flies fed on diets with high fat, high sugar or both.
Lim HY, Wang W, Chen J, Ocorr K, Bodmer R. ROS Regulate Cardiac Function via a Distinct Paracrine Mechanism. Cell Rep 2014. [Abstract] EPub
Lim HY, Bodmer R. Phospholipid homeostasis and lipotoxic cardiomyopathy: a matter of balance. Fly 5: 234-236, 2011. [Abstract]
Lim HY, Wang W, Wessells RJ, Ocorr K, Bodmer R. Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila. Genes Dev 25:189-200, 2011. [Abstract]
Ocorr K, Perrin L, Lim HY, Qian L, Wu X, Bodmer R. Genetic control of heart function and aging in Drosophila. Trends Cardiovasc Med 17:177-182, 2007. [Abstract]
Lim HY, Bodmer R, Perrin L. Drosophila aging 2005/06. Exp Gerontol 41:1213-1216, 2006. [Abstract]
Lim HY, Tomlinson A. Organization of the peripheral fly eye: the roles of Snail family transcription factors in peripheral retinal apoptosis. Development 133:3529-3537, 2006. [Abstract]
Lim HY, Seow KT, Li Q, Kesuma D, Wang JH, Qi RZ. Structural Insights into Cdk5 activation by a neuronal Cdk5 activator. Biochem Biophys Res Commun 285:77-83, 2001. [Abstract]
Free Radical Biology and Aging Research Program, MS 21
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-7575 or 271-7574
Fax: (405) 271-1437