Douglas R. Cavener

Douglas R. Cavener

Main Content

Professor and Verne M. Willaman Dean, Eberly College of Science

110 Life Sciences
University Park, PA 16802
Phone: (814) 865-4562
Lab Address: 113 Life Sciences
Lab Phone: (814) 865-1769
Email:

Education

  1. Ph.D., University of Georgia, 1980
  2. M.S., Brown University, 1977
  3. B.A., Pasadena College, 1973

Postdoc Training

  1. Cornell University, 1980-1982

Honors and Awards

  1. Theodosius Dobzhansky Prize, International Society for the Study of Evolution
  2. Fellow of the American Association for the Advancement of Science

Research Interests

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 processes that are particularly prone to maladaptations that lead to diseases such as diabetes and metabolic syndrome. In particular we are studying the regulatory role of PERK eIF2 alpha kinase. We have discovered that PERK is a dynamic sensor of physiological/developmental changes and acts to modulate genetic networks for the purpose of adaptation and to acutely regulate calcium intracellular calcium dynamics. 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 on PERK regulation of insulin synthesis, quality control, and secretion in the pancreatic beta cells and how this regulation controls whole body glucose homeostasis.

In addition to examining adaptive genetic regulatory networks in model organism, we are investigating the adaptations underlying the unique morphology and physiology of the giraffe. We have sequenced the giraffe genome as well as a closely related species okapi, which lacks giraffe unique morphology and turbocharged cardiovascular system. By using comparative genome analysis we have identified candidate genes that we propose underlies giraffe long neck and legs and associated cardiovascular adaptations. Current studies are focused on genetically and biochemically testing the function of these genes as related to giraffe's unique adaptations.

Selected Publications

Hussien Y, Cavener DR, Popko B. Genetic inactivation of PERK signaling in mouse oligodendrocytes: normal developmental myelination with increased susceptibility to inflammatory demyelination. Glia. 2014 62:680-91. PubMed PMID: 24481666.

Trinh MA, Ma T, Kaphzan H, Bhattacharya A, Antion MD, Cavener DR, Hoeffer CA, Klann E. The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression. Learn Mem. 2014 21:298-304. PubMed PMID: 24741110.

Liu X, Kwak D, Lu Z, Xu X, Fassett J, Wang H, Wei Y, Cavener DR, Hu X, Hall J, Bache RJ, Chen Y. Endoplasmic Reticulum Stress Sensor Protein Kinase R-Like Endoplasmic Reticulum Kinase (PERK) Protects Against Pressure Overload-Induced Heart Failure and Lung Remodeling. Hypertension. 2014 PubMed PMID: 24958502.

Wang R, Munoz EE, Zhu S, McGrath BC, Cavener DR. Perk gene dosage regulates glucose homeostasis by modulating pancreatic β-cell functions. PLoS One. 2014 9:e99684. PubMed PMID: 24915520

 

Wang R, McGrath BC, Kopp RF, Roe MW, Tang X, Chen G, Cavener DR. (2013) Insulin secretion and Ca2+dynamics in β-cells are regulated by PERK (EIFAK3) in concert with calcineurin. J Biol Chem. 288:33824-36. PMCID: PMC3837125.

Ma, T., Trinh, M. A., Wexler, A. J., Bourbon, C. Gatti, E., Pierre, P., Cavener, D. R.,  Klann, E. (2013) Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nature Neuroscience 16:1299-1305.

Xu, X., Hu, J., McGrath, B.C., Cavener D. R. (2013). GCN2 regulates the CCAAT enhancer binding  protein beta and hepatic gluconeogenesis. Am. J. Physiol. Endocrinol. Metab. 15;305(8):E1007-17.

Saito A., Ochiai K., Kondo S., Tsumagari K., Murakami T., Cavener D.R., Imaizumi K.(2011) Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 286:4809-18. PMCID: PMC3039352.

 

Gupta, S., McGrath, B.C., and Cavener, D.R. (2010) PERK regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59: 1937-1947.

 

Dang Do AN, Kimball SR, Cavener DR, Jefferson LS. (2009) The eIF2{alpha} Kinases GCN2 and PERK Modulate the Transcription and Translation of Distinct Sets of mRNAs in Mouse Liver. Physiol Genomics. 38:328-41.

 

Wei, J., Sheng, X., Feng, D., McGrath, B.C., and Cavener, D.R.  PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. (2008) J. Cell Physiol. 217: 693-707.

 

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.