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2008 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report • Imaging and isolation of primary dopaminergic neurons from mouse brain. Brendan Looyenga has performed a genetic cross between the DAT-cre strain and ROSA26 reporter strain to generate mice that specifically express the LacZ reporter gene in dopaminergic neurons. The DAT-cre/ROSA26 mice will permit us to visualize and quantify live dopaminergic neurons in vivo. With these mice we will assess the effect of cytotoxic agents (e.g., MMTP, rotenone, or 6-hydroxydopamine) on the number of dopaminergic cells, and more importantly, assess the ability of mice to recover from these insults. These studies will provide insight into the regenerative capacity of the brain when dopaminergic neurons are lost or injured. The DAT-cre/ROSA26 mice will also provide a source of highly pure dopaminergic neurons for in vitro studies. • Dopaminergic cell regeneration as a function of age. The relationship between age and the likelihood of developing Parkinson disease is well established, though the causal nature of this relationship is unclear. One hypothesis is that the capacity of the brain to regenerate damaged neurons decreases with age, consistent with a gradual loss of brain stem cells that give rise to new dopaminergic neurons. To test this hypothesis in a mammalian system, we will cross DAT-cre and puDTK mice, the latter specifically expressing herpes simplex virus thymidine kinase (hsvTK) in cells that contain cre recombinase. Cells expressing hsvTK are sensitive to ganciglovir (G418) and undergo programmed cell death after systemic treatment. Using the DAT-cre/ puDTK model, we will eliminate dopaminergic neurons at various ages and assess the regenerative potential of these mice. These studies will provide information about the value of therapies intended to stimulate the endogenous regenerative capacity of the brain in Parkinson disease patients. • Effect of hypoxia-inducible factor signaling on dopaminergic cell survival. Dopaminergic neurons are exquisitely sensitive to oxidative stress (reactive oxygen species), which can lead to cell death by direct mechanisms, such as damage to important cellular biomolecules, and indirect ones, such as the induction of cell death pathways. The latter mechanism may be offset by cell survival pathways, which increase the threshold signal intensity required to induce cell death. Because Parkinson disease is characterized by increased oxidative stress in dopaminergic neurons, therapies that increase cell survival pathways in these neurons may be broadly applicable to decrease cell death in patients. Other highlights Our GRAPCEP mentorship program continues for an eighth year and is now funded by Schering Plough. This year we had three students from GRAPCEP. Dr. Resau is a member of the graduate school committee that established the VAEI Graduate School, which will increase our research and educational opportunities. Also in 2007, Jim Resau had an image selected as one of the Nikon Small World top 100 images (see p.19), and Bree Berghuis, working with Carrie Graveel, had an image of cMet staining selected for the June 2008 Ventana Calendar. From left: Olinger, Luo, Hudson, Jason, Carruthers, Berghuis, Resau, Goolsby, Ramirez, Kort, VandenBeldt, Looyenga 44

VARI | 2008 Recent Publications Haak, P., J. Busik, E. Kort, M. Tikhonenko, N. Paneth, and J. Resau. In press. Archived unfrozen neonatal blood spots are amenable to quantitative gene expression analysis. Neonatology. Ding, Yan, Elissa A. Boguslawski, Bree D. Berghuis, John J. Young, Zhongfa Zhang, Kim Hardy, Kyle Furge, Eric Kort, Arthur E. Frankel, Rick V. Hay, James H. Resau, and Nicholas S. Duesbery. 2008. Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma. Molecular Cancer Therapeutics 7(3): 648–658. Huang, Dan, Yan Ding, Wang-Mei Luo, Stephanie Bender, Chao-Nan Qian, Eric Kort, Zhong-Fa Zhang, Kristin VandenBeldt, Nicholas S. Duesbery, James H. Resau, and Bin Tean Teh. 2008. Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo. Cancer Research 68(1): 81–88. Baldus, Stephan E., Eric J. Kort, Peter Schirmacher, Hans P. Dienes, and James H. Resau. 2007. Quantification of MET and hepatocyte growth factor/scatter factor expression in colorectal adenomas, carcinomas and non-neoplastic epithelia by quantitative laser scanning microscopy. International Journal of Oncology 31(1): 199–204. Depeille, Philippe, John J. Young, Elissa A. Boguslawski, Bree D. Berghuis, Eric J. Kort, James H. Resau, Arthur E. Frankel, and Nicholas S. Duesbery. 2007. Anthrax lethal toxin inhibits growth of and vascular endothelial growth factor release from endothelial cells expressing the human herpes virus 8 viral G protein–coupled receptor. Clinical Cancer Research 13(19): 5926–5934. Li, Zheng, Shireesh Srivastava, Xuerui Yang, Sheenu Mittal, Paul Norton, James Resau, Brian Haab, and Christina Chan. 2007. A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells. BMC Systems Biology 1: 15 pp. Lindemann, K., J. Resau, J. Nährig, E. Kort, B. Leeser, K. Anneke, A. Welk, J. Schäfer, G. F. Vande Woude, E. Lengyel, and N. Harbeck. 2007. Differential expression of c-Met, its ligand HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue. Histopathology 51(1): 54–62. Ott, Mickey, Alan T. Davis, Wayne VanderKolk, James H. Resau, David H. DeHeer, Clifford B. Jones, Chad Stouffer, and Edward W. Kubek. 2007. The protective effect of the blood brain barrier from systemic cytokines in an animal femur fracture model. Journal of Trauma 63(3): 591–595. Whitwam, T., M.W. VanBrocklin, M.E. Russo, P.T. Haak, D. Bilgili, J.H. Resau, H.-M. Koo, and S.L. Holmen. 2007. Differential oncogenic potential of activated RAS isoforms in melanocytes. Oncogene 26(31): 4563–4570. Young, John J., Jennifer L. Bromberg-White, Cassandra R. Zylstra, Joseph T. Church, Elissa Boguslawski, James H. Resau, Bart O. Williams, and Nicholas S. Duesbery. 2007. LRP5 and LRP6 are not required for protective antigen–mediated internalization or lethality of anthrax lethal toxin. PLoS Pathogens 3(3): e27. Zhao, Ping, Tessa Grabinski, Chongfeng Gao, R. Scot Skinner, Troy Giambernardi, Yanli Su, Eric Hudson, James Resau, Milton Gross, George F. Vande Woude, Rick Hay, and Brian Cao. 2007. Identification of a Met-binding peptide from a phage display library. Clinical Cancer Research 13(20): 6049–6055. 45

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