Department of Medicine
University of Pittsburgh
Christopher O'Donnell, PhD
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Professor of Medicine Phone: 412-648-9379 |
Bio
Dr. O’Donnell received his undergraduate training at the University of Otago, New Zealand, graduating with First Class Honors in Physiology in 1984. He was awarded a Commonwealth Scholarship for graduate training at the University of Cambridge, England, where he completed his Ph.D. in Physiology in 1988. Dr. O’Donnell received an American Heart Association Fellowship to pursue post-doctoral training in the Physiology Department of the University of California, San Francisco from 1988-1991. His first faculty appointment was at Johns Hopkins Medical School in 1991, where he was promoted from Instructor through to Associate Professor before leaving to join the University of Pittsburgh in July, 2004. He is currently an Associate Professor of Medicine in the Division of Pulmonary, Allergy, and Critical Care Medicine as well as Associate Professor of Cell Biology and Physiology. He is currently Chairman of the NIH Respiratory Integrative Biology and Translational Research (RIBT) study section and Associate Editor of the journals Obesity and Journal of Applied Physiology.
Academic and Research Interests
Dr. O’Donnell’s interests are in the pathophysiology of sleep apnea and its relationship to metabolic and cardiovascular dysfunction. His laboratory utilizes murine models of obesity and intermittent hypoxia (IH) using a variety of chronically instrumented inbred and transgenic mouse strains. In respiratory studies, he has established in the genetically obese ob/ob mouse that leptin deficiency leads to respiratory depression, and that leptin replacement can correct this respiratory depression independent of weight, food intake or metabolism. In metabolic studies, he has demonstrated that lean mice can exhibit insulin resistance and hyperlipidemia during exposure to IH as well as leading to a compensatory increase in pancreatic beta cell replication. In cardiovascular studies, Dr. O’Donnell and colleagues are currently determining the impact of heart failure on disruption of sleep architecture, and examining how the upregulation of cardiac leptin signaling plays a crucial role in reducing morbidity and mortality in response to myocardial ischemia.
Dr. O’Donnell has developed the ability to record sleep (polysomongraphy) in mice and to score the sleep in real-time using the computer-generated algorithms shown above. Using this real-time sleep assessment it is possible to expose mice to hypoxia only during sleep and restore the animals to normal room air breathing when they arouse or wake from sleep in response to the hypoxia. As a result he can specifically model the sleep-induced hypoxia that occurs in patients experiencing obstructive sleep apnea, which is characterized by repetitive periods of airway obstruction and intermittent hypoxia during sleep.
Chronic exposure to hyperglycemia is known to lead to a compensatory increase in pancreatic beta cell replication; a response can elevate circulating insulin levels and potentially lower blood glucose. Dr. O’Donnell and colleagues in the Division of Endocrinology and Metabolism have now shown that exposure to intermittent hypoxia (IH) can also produce pancreatic beta cell replication at a rate comparable to hyperglycemia, but the combination of glucose and IH (Glu + IH) was no more effective than either hyperglycemia or hypoxia alone. Since apoptosis (TUNEL (+) beta cells) was minimal during hypoxia it was concluded that IH leads to a compensatory increase in beta cell replication that mimics hyperglycemia. This finding is somewhat counterintuitive to endocrinologists who make every effort to avoid hypoxic exposure of beta cells being prepared for transplantation into diabetic patients. The O’Donnell laboratory is currently investigating the mechanisms through which IH can cause beta-cell proliferation and whether they share any common pathways with hyperglycemia-induced proliferation.
Leptin is a hormone primarily released from adipose tissue that has multiple systemic effects including suppressing appetite and increasing metabolism. However, leptin is also produced in many tissues other than the central nervous system, which have their own leptin receptor/signal transduction pathways. Dr. O’Donnell and colleagues in the Cardiovascular Institute have shown in mouse models of experimentally-induced heart failure that leptin deficiency leads to increased morbidity and mortality and that leptin administration can reverse this pathological phenotype. Moreover, the experimentally-induced heart failure causes increased production of leptin in cardiac myocytes and the translocation of leptin receptors to the cell membrane of myocytes. The figure above shows leptin receptors (red) in cardiac myocytes (green nuclei) in patients with heart failure (right panel) and control subjects without heart failure (left panel). The same pattern of response was seen in human heart failure – activation of leptin signaling pathways in cardiac myocytes – as in the murine model of heart failure. Dr. O’Donnell and colleagues are currently exploring the hypothesis that leptin may act as a metabolic switch in ischemic cardiac tissue to optimize the fuel source needed to maintain viability of the myocyte.
Key Publications
McGaffin, K.R., C.K. Sun, J.J. Rager, L.C. Romano, B. Zou, M.A. Mathier, R.M. O’Doherty, C.F. McTiernan, C.P. O’Donnell. Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury. Cardiovas. Res. 77(1):54-63,2008.
Yokoe, T., L.C. Alonso, L.C. Romano, T.C. Rosa, R.M. O’Doherty, A. Garcia-Ocana, K. Minoguchi, and C.P. O'Donnell. Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic beta cell replication in mice. J. Physiol. 586:899-911, 2008.
Iiyori, N, L.C. Alonso, J. Li, M.H. Sanders, A. Garcia-Ocana, R.M. O’Doherty, V.Y. Polotsky, and C.P. O'Donnell. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am. J. Resp. Crit. Care Med. 175:851-857, 2007.
Alonso, L.C., T. Yokoe, P. Zhang, D.K. Scott, S.K. Kim, C.P. O’Donnell, and A. Garcia-Ocana. Glucose infusion in mice: a new model to induce beta-cell replication. Diabetes. 56(7):1792-801, 2007.
Raju, S.V, M. Zheng, K.H. Schuleri, A.C. Phan, D. Bedja, R.M. Saraiva, O. Yiginer, K. Vandegaer, K.L. Gabrielson, C.P. O’Donnell, D.E. Berkowitz, L.A. Barouch, J.M. Hare. Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity. P.N.A.S. 103(11):4222-4227, 2006.
Li, J. L.N. Thorne, N.M. Punjabi, C.K. Sun, A.R. Schwartz, P.L. Smith, R.L. Marino, A. Rodriguez, W.C. Hubbard, C.P. O’Donnell, and V.Y. Polotsky. Intermittent hypoxia induces hyperlipidemia in lean mice Circ. Res.97:698-706, 2005.
Campen M.J., Y. Tagaito, J. Li, A. Balbir, C.G. Tankersley, P.L. Smith, A.R. Schwartz, C.P. O'Donnell. Phenotypic variation in cardiovascular responses to acute hypoxic and hypercapnic exposure in mice. Physiol Genomics. 20:15-20, 2004.
Barouch, L.A., D.E. Berkowitz, R.W. Harrison, C.P. O’Donnell, and J.M. Hare. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 108:754-759, 2003.
Rubin, A.E, , V.Y. Polotsky, A. Balbir, J.A. Krishnan, A.R. Schwartz, P.L. Smith, R.S. Fitzgerald, C.G. Tankersley, M. Shirahata, C.P. O'Donnell. Differences in sleep-induced hypoxia between A/J and DBA/2J mouse strains. Am. J. Resp. Crit. Care Med. 168:1520-7, 2003.
Tagaito, Y., V.Y. Polotsky, M.J. Campen, J.A. Wilson, A., Balbir, P.L. Smith, A.R. Schwartz, and C.P. O'Donnell. A model of sleep disordered breathing in the C57BL/6J mouse. J. Appl. Physiol. 91:2758-66, 2001.
Polotsky, V.Y., J.A. Wilson, A.S. Haines, M.T. Scharf, S.E. Soutiere, C.G. Tankersley, P.L. Smith, A.R. Schwartz, and C.P. O’Donnell. The impact of insulin-dependent diabetes on ventilatory control in the mouse. Am. J. Respir. Crit. Care Med. 163:624-632, 2001.
O’Donnell, C.P., C.D. Schaub, A.S. Haines, C.G. Tankersley, A.R. Schwartz, and P.L. Smith. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 159(5): 1477-1484, 1999.