Abstract

This proposal builds on the enzyme chemical and technical knowledge we have accumulated over the past years regarding the role of Factor XIII in blood clotting, and it is oriented towards studying molecular defects of fibrin stabilization in patients. Malfunctioning of the fibrin stabilizing factor system often leads to severe hemorrhaging, and a number of unique cases are under analysis. In addition, we propose to improve and automate Factor XIII assays for testing large numbers of human plasma samples in order to weigh fluctuations of activity of this factor in health and disease. Activity data will be matched against the immunological testing of Factor XIII proteins (a and b subunits). A comprehensive approach aimed at standardizing purified Factor XIII zymogen preparations will be explored for therapeutic purposes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL016346-16
Application #
3335178
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-05-01
Project End
1988-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
16
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Type
Schools of Arts and Sciences
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60208

  Publications

Lefebvre, Phil; Velasco, Pauline T; Dear, Amy et al. (2004) Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk). Blood 103:2571-6
Iismaa, Siiri E; Holman, Sara; Wouters, Merridee A et al. (2003) Evolutionary specialization of a tryptophan indole group for transition-state stabilization by eukaryotic transglutaminases. Proc Natl Acad Sci U S A 100:12636-41
O'Neill, Gerald M; Prasanna Murthy, S N; Lorand, Laszlo et al. (2003) Activation of transglutaminase in mu-calpain null erythrocytes. Biochem Biophys Res Commun 307:327-31
Lorand, Laszlo; Velasco, Pauline T; Hill, John M et al. (2002) Intracranial hemorrhage in systemic lupus erythematosus associated with an autoantibody against actor XIII. Thromb Haemost 88:919-23
Lorand, Laszlo (2002) Transglutaminase: remembering Heinrich Waelsch. Neurochem Int 40:7-12
Lorand, L (2001) Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann N Y Acad Sci 936:291-311
Lorand, L (2000) Sol Sherry Lecture in Thrombosis : research on clot stabilization provides clues for improving thrombolytic therapies. Arterioscler Thromb Vasc Biol 20:9-Feb
Lorand, L; Velasco, P T; Murthy, S N et al. (1999) Autoimmune antibody in a hemorrhagic patient interacts with thrombin-activated factor XIII in a unique manner. Blood 93:909-17
Lorand, L; Parameswaran, K N; Murthy, S N (1998) A double-headed Gly-Pro-Arg-Pro ligand mimics the functions of the E domain of fibrin for promoting the end-to-end crosslinking of gamma chains by factor XIIIa. Proc Natl Acad Sci U S A 95:537-41
Parameswaran, K N; Cheng, X F; Chen, E C et al. (1997) Hydrolysis of gamma:epsilon isopeptides by cytosolic transglutaminases and by coagulation factor XIIIa. J Biol Chem 272:10311-7

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