- Ph.D., University of Georgia, 1980
- M.S., Brown University, 1977
- B.A., Pasadena College, 1973
- Cornell University, 1980-1982
Honors and Awards:
- Theodosius Dobzhansky Prize, International Society for the Study of Evolution
Adaptive Genetic Regulatory Networks
My research interests encompass genetic regulatory pathways that dynamically control developmental and physiological processes to adapt to internal or external perturbations. Currently, my research group is focused on regulation of metabolic and neurological processes that are particularly prone to maladaptations that lead to diseases such as diabetes, metabolic syndrome, and neurodegenerative diseases. We are investigating two key protein kinases, GCN2 and PERK, which phosphorylate the translation initiation factor eIF2 alpha. These kinases are dynamic sensors of physiological/developmental changes and act to modulate genetic networks for the purpose of adaptation. The importance of PERK was underscored by our finding that mice genetically deficient for PERK display permanent neonatal diabetes, exocrine pancreas atrophy, multiple skeletal dysplasias, severe metabolic dysfunctions, and growth retardation. The phenotype of the Perk knockout mouse parallels the human Wolcott-Rallison syndrome, also caused by Perk deficiency. Current research is focused in two areas: (1) regulation of insulin synthesis, quality control, and secretion in the pancreatic beta cell, and (2) regulation of neurological functions, particularly with respect to neurodegenerative disorders such as Alzheimer’s disease.
GCN2 is expressed in a variety of tissues, including the liver and brain. Our group has collaborated with other researchers to show that GCN2 is a key sensor of dietary amino acids in the brain that has direct effects on feeding behavior (Science 2005 307:1776). More recently, we found that GCN2-deficient mice exhibit a deficiency in lipid storage in the liver, which has a secondary consequence of severe hypertriglyceridemia and insulin resistance. These metabolic dysfunctions arise from maternal programming that is dependent upon the maternal diet. Unexpectedly, we have found that GCN2-dependent programming of lipid storage in the liver is controlled by GCN2 functions in the brain, which, in turn, communicates with the liver.
A key genetic tool that we employ in our research is the use of conditional (tissue or stage-specific) gene knockouts in mice using the Cre/loxP site-specific recombination system, which we have introduced into the mouse genome. These conditional knockout mutations allow us to examine the function of these genes in isolation of other defects and to determine whether such defects are cell autonomous. Our genetic analysis of mice is complemented by cell culture experiments utilizing a variety of cell types to investigate the molecular basis of gene function and regulation.
Our research has direct biomedical implications for several human diseases, including diabetes, neurological disorders, cancer, osteoporosis, and growth defects. Many such diseases are caused by developmental and physiological defects that arise in late fetal and early neonatal development as organisms transition from in utero development, dominated by the developmental program and maternal environment, to neonatal-juvenile development, which rapidly test the ability of the newly developed organ systems to grow and mature and carry out normal physiological functions. We are learning that PERK and GCN2, as key regulators of gene expression, are particularly important during these critical developmental-physiological transitions.
Gupta, S., B. C. McGrath, and D. R. Cavener. 2010. PERK regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59: 1937-1947.
Gupta, S., B. C. McGrath, and D. R. Cavener. 2009. PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas in mice. PLoS One 4: 8008.
Bobrovnikova-Marjon, E., G. Hatzivassiliou, C. Grigoriadou, M. Romero, D. R. Cavener, C. B. Thompson, and J. A. Diehl. 2008 PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocytes differentiation. Proc. Natl. Acad. Sci. 105: 16314-163419.
Wei, J., X. Sheng, D. Feng, B. C. McGrath, and D. R. Cavener. 2008. PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. J. Cell Physiol. 217: 693-707.
Guo, F. and D. R. Cavener. 2007. The GCN2 eIF2a kinase regulates fatty acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metabolism 5: 103-114.
Zhang, W., D. Feng, Y. Li, K. Iida, B. McGrath, and D. R. Cavener. 2006. PERK EIF2AK3 control of pancreatic b-cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metabolism 4: 491-497.
Hao, S., J. W. Sharp, C. M. Ross-Inta, B. J. McDaniel, T. G. Anthony, R. C. Wek, D. R. Cavener, B. C. McGrath, J. B. Rudell, T. J. Koehnle, and D. W. Gietzen. 2005. Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307: 1776-1778.
Li, Y., K. Iida, J. O'Neil, P. Zhang, S. Li, A. Frank, A. Gabai, F. Zambito, S.-H. Liang, C. J. Rosen, and D. R. Cavener. 2003. PERK eIF2 alpha kinase regulates neonatal growth by controlling the expression of circulating Insulin-like growth factor-1 derived from the liver. Endocrinology 144(8): 3505-3513.
Zhang, P., B. C. McGrath, J. Reinert, D. S. Olsen, L. Lei, S. Gill, K. M. Vattem, R. C. Wek, S. R. Kimball, L. S. Jefferson, and D. R. Cavener. 2002. The GCN2 eIF2 alpha kinase is required for adaptation to amino acid deprivation in mice. Mol. Cell. Biol. 22: 6681-6688.
Zhang, P., B. McGrath, S. Li, A. Frank, F. Zambito, J. Reinert, M. Gannon, K. Ma, K. McNaughton, and D. R. Cavener. 2002. The PERK eIF2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell. Biol. 22: 3864-3874.