Francis J. Castellino, PhD

Director, W.M. Keck Center for Transgene Research
Kleiderer-Pezold Professor of Biochemistry
Department of Chemistry and Biochemistry
Dean emeritus, College of Science
University of Notre Dame

Adjunct Professor, Department of Biochemistry and Molecular Biology
Indiana University School of Medicine, South Bend, Indiana

Education
BS, University of Scranton, 1964
MS, University of Iowa, 1966
PhD, University of Iowa, 1968
Postdoctoral fellow, Duke University, 1968-1970

Address
W. M. Keck Center for Transgene Research
230 Raclin-Carmichael Hall
University of Notre Dame
Notre Dame, IN 46556

Contact
Phone: (574) 631-8996
Fax: (574) 631-8017
E-mail: fcastell@nd.edu

Honors and Awards

1966-1968 NIH Predoctoral Fellowship
1968-1970 NIH Postdotoral Fellowship
1974-1979 NIH Research Career Development Award
1974-1979 Camille and Henry Dreyfus Teacher-Scholar Award
1982 Honorary LL.D., University of Scranton
1983 Akron section of the A.C.S. Research Award
1989 Frank O’Hara Award in Education, University of Scranton National Alumni Society
1990 Merit Award (HL-13423), NHLBI, National Institutes of Health
1992 Annual Undergraduate Lecture, University of Waterloo, Waterloo, Ontario, Canada
1994 Annual Graduate School Award, University of Notre Dame
1994 Commencement Address, University of Waterloo, Waterloo, Ontario, Canada
1994 Honorary D.Sc., University of Waterloo, Waterloo, Ontario, Canada
1995 Educator of the Year Award, Michiana Executive Journal
2003 Annual University Faculty Award, University of Notre Dame

Memberships and Committees
1982-1985 Member, NIH Biomedical Sciences Study Section
1983 Elected Fellow of the N. Y. A. S.
1988 Elected Fellow of the A. A. A. S.
1990 Member, Parent Committee on SCOR Proposals in Thrombosis (NIH)
1990-1994 Member and Chair (1990-1992), NIH Hematology 2 Study Section
2001 Elected Fellow of the American Heart Association and the Council on Thrombosis
2002 Department of Chemistry and Biochemistry Committee on Appointments and Promotions
2005 College of Science Committee on Faculty Grievance
2005 University Committee on Appeals
2005 Faculty Athletic Board
2006 Fellow of the Reilly Center for Science, Technology, and Values, University of Notre Dame

Other Activities

1996 Editorial Boards, Journal of Biological Chemistry; Biotechnology and Applied Biochemistry
1998 Editor-in-Chief, Current Drug Targets

Research Focus

The overall interests of Professor Castellino's laboratory are centered on the in vitro and in vivo relationships between hemostasis and inflammation. More specifically, the function and activation of proteins that participate in blood coagulation, anticoagulation, and blood clot dissolution are studied at the protein and gene levels using modern biochemical and biophysical techniques, e.g., cloning, mutagenesis and expression of variant recombinant proteins and individual protein domains, immunochemistry, and physical and chemical studies of their structures, employing X-ray crystallography, NMR, calorimetry. The properties of the proteins are then related to their functions. This work is then carried to the gene, cellular, and whole animal levels with the aim of understanding the cross-communications between the blood clotting system and the inflammatory response. Here, appropriate acute and chronic inflammatory disease models (e.g., sepsis/endotoxemia, atherosclerosis, asthma, cancer) are investigated in genetically-altered mice to attempt to mechanistically understand the pathophysiology of these diseases. Major tools employed in these studies include construction and utilization of in vivo gene-targeted and traditional transgenic mice, cell-specific gene microarray studies, organ- and cell-specific imaging, histology, and sophisticated mouse surgical approaches.

Another set of projects receiving attention involves the structure-function relationships of small gamma-carboxyglutamic acid (Gla)-containing peptides from marine cone snails that target the brain NMDA receptor. These peptides inhibit the flow of calcium into neuronal cells, and this latter event is at least in-part responsible for the neuropathologies associated with stroke, epilepsy, Alzheimer's Disease, ALS, etc. The biochemical, pharmacological, and neurobiological mechanisms of the actions of these peptides are under study. Peptide synthesis, receptor binding, molecular biological, and electrophysiological tools are currently employed in this research.

Selected Recent Publications

Balsara RD, Merryman R, Virjee F, Northway C, Castellino FJ, Ploplis VA. (2011).  A deficiency of uPAR alters endothelial angiogenic function and cell morphology.  Vasc Cell. 2:3:10.

Dai Q, Dong M, Liu Z, Prorok M, Castellino FJ.  (2011)  Ca 2+-induced self assembly in designed peptides with optimally spaced gamma-carboxyglutamic acid residues.  J Inorg Biochem. 105:52-57.

Cnudde SE, Prorok M, Jia X, Castellino FJ, Geiger JH. (2011)  The crystal structure of the calcium-bound con-G[Q6A] peptide reveals a novel metal-dependent helical trimer.   J Biol Inorg Chem. 16:257-266.

Castellino FJ, Donahue DL, Navari RM, Ploplis VA, Walsh M.  (2011).  An accompanying genetic severe deficiency of tissue factor protects mice with a protein C deficiency from lethal endotoxemia.  Blood.  117: 283-289

Kerschen E, Hernandez I, Zogg M, Jia S, Hessner MJ, Fernandez JA, Griffin JH, Huettner CS, Castellino FJ, Weiler H.  (2010)  Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice.  J Clin Invest.  120:3167-3178

Sheng Z, Prorok M, Castellino FJ.  (2010)  Specific determinants of conantokins that dictate their selectivity for the NR2B subunit of N-methyl-D-aspartate receptors.  Neuroscience.  170:703-710.

Wang M, Prorok M, Castellino FJ.  (2010)  NMR backbone dynamics of VEK-30 bound to the human plasminogen kringle 2 domain.  Biophys J.  99:302-312.

Iwaki T, Malinverno C, Smith D, Xu Z, Liang Z, Ploplis VA, Castellino FJ. (2010).  The generation and characterization of mice expressing a plasmin-inactivating active site mutation.  J Thromb Haemost. 8:2341-2344.

Huang L, Balsara RD, Sheng Z, Castellino FJ.  (2010)  Conantokins inhibit NMDAR-dependent calcium influx in developing rat hippocampal neurons in primary culture with resulting effects on CREB phosphorylation.  Mol Cell Neurosci.   45:163-172.

Cao C, Gao Y, Li Y, Antalis TM, Castellino FJ, Zhang L.  (2010) The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b.  J Clin Invest. 120:1971-1980.

Xu Z, Xu H, Ploplis VA, Castellino FJ. (2010). Factor VII deficiency impairs cutaneous would healing in mice.  Mol Med. 16:167-176

Cnudde SE, Prorok M, Castellino FJ, Geiger JH.  (2010)  Metal ion determinates of conantokin dimerization as revealed in the X-ray crystallographic structure of the Cd(2+_/Mg (2+)-con-T[K7gamma] complex.  J Biol Inorg Chem. 15:667-675.

Figuera-Losada M, Ranson M, Sanderson-Smith ML, Walker MJ, Castellino FJ, Prorok M.  (2010)  Effects on human plasminogen conformation and activation rate caused by interaction with VEK-30, a peptide derived from the group A streptococcal M-like protein (PAM).  Biochim Biophys Acta.   1804:1342-1349.

Guillen-Ahlers H, Suckow MA, Castellino FJ, Ploplis VA.  (2010)  Fas/CD95 defieciency in ApcMin/+ mice increases intestinal tumor burden.  PLoS One.  5:e9070

Danese S, Vetrano S, Zhang L, Poplis VA, Castellino FJ.  (2010)  The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications.  Blood.  115:1121-1130.

Xu Z, Castellino FJ, Ploplis VA.  (2010)  Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture.  Blood.  115:2038-2047.

Wang M, Zajicek J, Geiger JH, Prorok M, Castellino FJ.  (2010)  Solution structure of the complex of VEK-30 and plasminogen kringle 2.  J Struct Biol.  169:349-359. 

Wang M, Zajicek J, Geiger JH, Prorok M, Castellino FJ.  (2010)  Solution structure of the complex of VEK-30 and plasminogen kringle 2.  J Struct Biol.  169:349-359.

Zhong Z, Ilieva H, Hallagan L, Bell R, Singh I, Paquette N, Thiyagarajan M, Deane R, Fernandez JA, Lane S, Zlokovic AB, Liu T, Griffin JH, Chow N, Castellino FJ, Stojanovic K, Cleveland DW, Zlokovic BV.  (2009) Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells.  J Clin Invest.  119:3437-3449.

Battistel MD, Grishaev A, An SS, Castellino FJ, Llinás M.  (2009)  Solution structure and functional characterization of human plasminogen kringle 5.  Biochemistry. 48:10208-10219.

Gutiérrez-Fernández A, Gingles NA, Bai H, Castellino FJ, Parmer RJ, Miles LA.  (2009)  Plasminogen enhances neuritogenesis on laminin-1.  J Neurosci.   29:12393-12400.

Waldemarsson J, Stålhammar-Carlemalm M, Sandin C, Castellino FJ, Lindahl G.  (2009)  Functional dissection of Streptococcus pyogenes M5 protein: the hypervariable region is essential for virulence.  PLoS One.   4:e7279.

Castellino FJ, Ploplis VA.  (2009)  The protein C pathway and pathologic processes.  J Thromb Haemost  7 Suppl 1:140-145

Dai Q, Xiao C, Dong M, Liu Z, Sheng Z, Castellino FJ, Prorok M.  (2009)  Non-strict strand orientation of the Ca2+-induced dimerization of a conantokin peptide variant with sequence-shifted gamma-carboxyglutamate residues.  Peptides.  30:866-872.

Sheng Z, Liang Z, Geiger JH, Prorok M, Castellino FJ.  (2009) The selectivity of conantokin-G for ion channel inhibition of NR2B subunit-containing NMDA receptors is regulated by amino acid residues in the S2 region of NR2B.   Neuropharmacology  57:127-136.

Shinagawa K, Ploplis VA, Castellino FJ.  (2009)  A severe deficiency of coagulation factor VIIa results in attenuation of the asthmatic response in mice.  Am J Physiol Lung Cell Mol Physiol. 296:L763-770.

Muralidharan-Chari V, Hoover H, Clancy J, Schweitzer J, Suckow MA, Schroeder V, Castellino FJ, Schorey JS, D'Souza-Schorey C.  (2009)  ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo.  Cancer Res.   69:2201-2209.

Tang H, Fu Y, Lei Q, Han Q, Ploplis VA, Castellino FJ, Li L, Luo Y.  (2009)  Fibrinogen facilitates the anti-tumor effect of nonnative endostatin. Biochem Biophys Res Commun.  380:249-253.

Niessen F, Furlan-Freguia C, Fernández JA, Mosnier LO, Castellino FJ, Weiler H, Rosen H, Griffin JH, Ruf W.  (2009)  Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality.  Blood.  113:2859-2866.

Tang H, Fu Y, Cui Y, He Y, Zeng X, Ploplis VA, Castellino FJ, Luo Y. (2009)  Fibrinogen has chaperone-like activity.  Biochem Biophys Res Commun.   378:662-667.

Xu H, Noria F, Sandoval-Cooper MJ, Menchen H, Donahue DL, Ploplis VA, Castellino FJ.  (2009)  Severe deficiency of coagulation Factor VII results in spontaneous cardiac fibrosis in mice. J Pathol.  217:362-371.