Washington University School of Medicine - Cardiovascular Division - Center for Cardiovascular Research
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Jean
E. Schaffer, M.D. Bio
Sketch Current Research
Recent Publications Professor of Medicine, Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, MO Clinical
Sciences Research Bldg., North Addition Harvard
College, Cambridge, MA, A.B., Biochemistry, 1982 Honors: 1978
National Merit Scholarship; Valedictorian, Shaker Heights High School
1980 American Cancer Society Student Fellowship The worldwide epidemic of diabetes and obesity presents a formidable challenge because of the serious cardiovascular complications of these disorders. Both diabetes and obesity are known risk factors for coronary artery disease, and diabetics often have a more clinically aggressive form of the disease than their non-diabetic counterparts. Cardiomyopathy, independent of coronary atherosclerosis, is a frequent complication that contributes significantly to increased morbidity and mortality amongst affected individuals. Evidence is emerging that in diabetic and obese individuals, dyslipidemia leads to fatty acid accumulation in non-adipose tissues such as the myocardium or endothelium, which results in cellular dysfunction and cell death and contributes to organ dysfunction, a process known as lipotoxicity. Similarly, dyslipidemia may contribute to other end organ complications and play a key role in transmitting increased cardiovascular risk to offspring. Not only are the risks for cardiovascular disease apparent in diabetic and obese individuals, but also epidemiological studies indicate that this risk is transmitted transgenerationally from obese and diabetic mothers to their offspring, in part through epigenetic influences of the intrauterine environment. The goals of studies in the Schaffer lab are to characterize the fundamental cellular mechanisms of lipotoxicity, and to understand how these processes contribute to organ dysfunction in rodent models of metabolic disease. Our studies involve genetic screens in cultured cells into identify key molecular players in the lipotoxic response, as well as experiments to elucidate the contributions of these genes and their products in genetic mouse models of obesity and diabetes and in transgenic mice with lipotoxic cardiomyopathy. In addition, we are working with colleagues to develop a murine model in which to study the role of the intrauterine environment as a determinant of metabolic syndrome, obesity and diabetes in adult offspring. The goal of these studies is to understand mechanisms of metabolic imprinting. In an effort to translate our basic studies to understanding human disease, we are collaborating with clinical investigators to define the correlates between altered systemic lipid metabolism and early diabetic cardiomyopathy in asymptomatic human subjects with type 2 diabetes. Our long-term goal is to develop novel lipid biomarkers and non-invasive methods for diagnosing the earliest structural and functional abnormalities in diabetic cardiomyopathy and for guiding therapy that may be applied to population-based practice. 2001 Listenberger L.L., Ory D.S., Schaffer JE. Palmitate-induced apoptosis occurs through a ceramide-independent pathway. J Biol Chem 276: 14890-14895. 2001 Chiu H-C., Kovacs A., Ford D.A., Hsu F.-F., Garcia R., Herrero P., Saffitz J.E., Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 107: 813-22. 2003 Listenberger LL, Han X, Lewis SL, Cases S, Farese RV, Ory DS, Schaffer JE. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 100: 3077-3082. 2006 Borradaile NM, Buhman KK, Listenberger LL, Magee CJ, Morimoto TA, Ory DS, Schaffer JE. A critical role for eukaryotic elongation factor 1A-1 in lipotoxic cell death. Mol Biol Cell 17: 770-778. 2006 Borradaile NM, Han X, Harp JD, Ory DS, Schaffer JE. Disruption of endoplasmic reticulum structure and integrity is central to lipotoxic cell death. J Lipid Res, 2006 47: 2726-2737.
Center
for Cardiovascular Research
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