Francis J Castellino, PhD

Director, Kleiderer-Pezold Professor of Biochemistry

Francis J - Castellino, PhD

Contact Info:

Phone: 574-631-8996
Email: fcastell@nd.edu

 

Biography

1996–present Director, WM Keck Center for Transgene Research, University of Notre Dame
1983–present Kleiderer/Pezold Professor of Biochemistry, University of Notre Dame
1979–2002 Dean, College of Science, University of Notre Dame
1977–1983 Professor, University of Notre Dame
1974–1977 Associate Professor, University of Notre Dame
1970–1974 Assistant Professor, University of Notre Dame
1968–1970 NIH Postdoctoral Fellow, Duke University
1968 Ph.D. Biochemistry, University of Iowa
1964 B.S. University of Scranton

Honors & Awards

2014 Distinguished alumnus, University of Iowa Carver School of Medicine
2008  Wyeth-ISPF Research Prize
2006 Fellow of the Reilly Center for Science, Technology, and Values
2003 Annual Faculty Award, University of Notre Dame
2001 Elected Fellow of the American Heart Association and the Council on Arteriosclerosis, Thrombosis, and Vascular Biology

Research Interests

My laboratory studies the structure, function and activation of proteins that participate in blood coagulation and blood clot dissolution. The in vivo mechanisms of the roles of these proteins in these processes are being addressed through in vivo targeted gene-replacement approaches and corresponding in vitro structure-function studies on these genes and proteins are being studied by the most modern biophysical techniques, e.g., X-ray crystallography, NMR, etc. Most of these proteins exist in an inactive state in plasma and thus must be activated to enzymes to exhibit their functional properties. The molecular events involved in the activation and analysis of the concomitant structural changes that occur in the protein are investigated by modern biochemical techniques. Major tools of the laboratory involve cloning, mutagenesis and expression of variant recombinant proteins and individual protein domains, immunochemical studies of the proteins, as well as physical and chemical analysis of their solution structures. The properties of the proteins are then related to their functions. One project 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, this latter event being responsible for the neuropathology 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 work. To determine the biological functions of genes encoding coagulation and clot-dissolving proteins in hemostasis, cancer, inflammation, bacterial invasion, wound healing, embryonic implantation and development, metastases, and atherosclerosis, gene deletion and other gene targeting experiments are being performed in mice, in conjunction with phenotyping of these animals. Such studies are expected to provide important information on the development and progression of these disease states.

Recent Papers

Gupta KK, Donahue DL, Sandoval-Cooper MJ, Castellino FJ, Ploplis VA. Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation. Sci Rep. 2017 Mar 23;7(1):365. doi: 10.1038/s41598-017-00418-y. PMID: 28336948

Glinton K, Beck J, Liang Z, Qiu C, Lee SW, Ploplis VA, Castellino FJ. Variable Region in Streptococcal M-Proteins Provides Stable Binding with Host Fibrinogen for Plasminogen-Mediated Bacterial Invasion. J Biol Chem. 2017 Mar 9. pii: jbc.M116.768937. doi: 10.1074/jbc.M116.768937. [Epub ahead of print] PMID: 28280245

Walsh M, Shreve J, Thomas S, Moore E, Moore H, Hake D, Pohlman T, Davis P, Ploplis V, Piscoya A, Wegner J, Bryant J, Crepinsek A, Lantry J, Sheppard F, Castellino F. Fibrinolysis in Trauma: "Myth," "Reality," or "Something in Between". Semin Thromb Hemost. 2017 Mar;43(2):200-212. doi: 10.1055/s-0036-1597900. Epub 2017 Feb 20. PMID: 28219085

Bao YJ, Shapiro BJ, Lee SW, Ploplis VA, Castellino FJ. Phenotypic differentiation of Streptococcus pyogenes populations is induced by recombination-driven gene-specific sweeps. Sci Rep. 2016 Nov 8;6:36644. doi: 10.1038/srep36644. PMID: 27821851

Higashi DL, Biais N, Donahue DL, Mayfield JA, Tessier CR, Rodriguez K, Ashfeld BL, Luchetti J, Ploplis VA, Castellino FJ, Lee SW. Activation of band 3 mediates group A Streptococcus streptolysin S-based beta-haemolysis. Nat Microbiol. 2016 Jan 18;1:15004. doi: 10.1038/nmicrobiol.2015.4. PMID: 27571972

Bao YJ, Liang Z, Mayfield JA, McShan WM, Lee SW, Ploplis VA, Castellino FJ. Novel genomic rearrangements mediated by multiple genetic elements in Streptococcus pyogenes M23ND confer potential for evolutionary persistence. Microbiology. 2016 Aug;162(8):1346-59. doi: 10.1099/mic.0.000326. Epub 2016 Jun 21. PMID: 27329479

Gupta KK, Xu Z, Castellino FJ, Ploplis VA. Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4. Biochem Biophys Res Commun. 2016 Aug 26;477(3):503-8. doi: 10.1016/j.bbrc.2016.06.065. Epub 2016 Jun 15. PMID: 27317488

Mamczak CN, Maloney M, Fritz B, Boyer B, Thomas S, Evans E, Ploplis VA, Castellino FJ, McCollester J, Walsh M. Thromboelastography in Orthopaedic Trauma Acute Pelvic Fracture Resuscitation: A Descriptive Pilot Study. J Orthop Trauma. 2016 Jun;30(6):299-305. doi: 10.1097/BOT.0000000000000537. PMID: 27206253

Yasui H, Donahue DL, Walsh M, Castellino FJ, Ploplis VA. Early coagulation events induce acute lung injury in a rat model of blunt traumatic brain injury. Am J Physiol Lung Cell Mol Physiol. 2016 Jul 1;311(1):L74-86. doi: 10.1152/ajplung.00429.2015. Epub 2016 May 17. PMID: 27190065

Bao YJ, Liang Z, Mayfield JA, Donahue DL, Carothers KE, Lee SW, Ploplis VA, Castellino FJ. Genomic Characterization of a Pattern D Streptococcus pyogenes emm53 Isolate Reveals a Genetic Rationale for Invasive Skin Tropicity. J Bacteriol. 2016 May 27;198(12):1712-24. doi: 10.1128/JB.01019-15. Print 2016 Jun 15. PMID: 27044623

Walsh M, Fritz S, Hake D, Son M, Greve S, Jbara M, Chitta S, Fritz B, Miller A, Bader MK, McCollester J, Binz S, Liew-Spilger A, Thomas S, Crepinsek A, Shariff F, Ploplis V, Castellino FJ. Targeted Thromboelastographic (TEG) Blood Component and Pharmacologic Hemostatic Therapy in Traumatic and Acquired Coagulopathy. Curr Drug Targets. 2016;17(8):954-70. PMID: 26960340

Agrahari G, Liang Z, Glinton K, Lee SW, Ploplis VA, Castellino FJ. Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria. J Biol Chem. 2016 Apr 22;291(17):9181-9. doi: 10.1074/jbc.M115.704221. Epub 2016 Mar 4. PMID: 26945067

Bao YJ, Liang Z, Mayfield JA, Lee SW, Ploplis VA, Castellino FJ. CovRS-Regulated Transcriptome Analysis of a Hypervirulent M23 Strain of Group A Streptococcus pyogenes Provides New Insights into Virulence Determinants. J Bacteriol. 2015 Oct;197(19):3191-205. doi: 10.1128/JB.00511-15. Epub 2015 Jul 27. PMID: 26216843

Chandrahas V, Glinton K, Liang Z, Donahue DL, Ploplis VA, Castellino FJ. Direct Host Plasminogen Binding to Bacterial Surface M-protein in Pattern D Strains of Streptococcus pyogenes Is Required for Activation by Its Natural Coinherited SK2b Protein. J Biol Chem. 2015 Jul 24;290(30):18833-42. doi: 10.1074/jbc.M115.655365. Epub 2015 Jun 12. PMID: 26070561

Gupta KK, Donahue DL, Sandoval-Cooper MJ, Castellino FJ, Ploplis VA. Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia. PLoS One. 2015 Mar 23;10(3):e0120728. doi: 10.1371/journal.pone.0120728. eCollection 2015 Mar 23. PMID: 25799354

Bao Y, Liang Z, Booyjzsen C, Mayfield JA, Li Y, Lee SW, Ploplis VA, Song H, Castellino FJ. Unique genomic arrangements in an invasive serotype M23 strain of Streptococcus pyogenes identify genes that induce hypervirulence. J Bacteriol. 2014 Dec;196(23):4089-102. doi: 10.1128/JB.02131-14. Epub 2014 Sep 15. PMID: 25225265

Mayfield JA, Liang Z, Agrahari G, Lee SW, Donahue DL, Ploplis VA, Castellino FJ.Mutations in the control of virulence sensor gene from Streptococcus pyogenes after infection in mice lead to clonal bacterial variants with altered gene regulatory activity and virulence. PLoS One. 2014 Jun 26;9(6):e100698. doi: 10.1371/journal.pone.0100698. eCollection 2014 Jun 26. PMID: 24968349

k AJ, Ploplis VA, Law R, Castellino FJ. Dimerization is not a determining factor for functional high affinity human plasminogen binding by the group A streptococcal virulence factor PAM and is mediated by specific residues within the PAM a1a2 domain. J Biol Chem. 2014 Aug 1;289(31):21684-93. doi: 10.1074/jbc.M114.570218. Epub 2014 Jun 24. PMID:24962580

Castellino FJ, Chapman MP, Donahue DL, Thomas S, Moore EE, Wohlauer MV, Fritz B, Yount R, Ploplis V, Davis P, Evans E, Walsh M. Traumatic brain injury causes platelet adenosine diphosphate and arachidonic acid receptor inhibition independent of hemorrhagic shock in humans and rats. J Trauma Acute Care Surg. 2014 May;76(5):1169-76. doi: 10.1097/TA.0000000000000216. PMID: 24747445