Continuing objective is to transfer the specialized protein and enzyme chemical knowledge accumulated over the years in our laboratory on the factor XIII (fibrin stabilizing factor) and similarly acting transaminating enzyme systems, when transglutaminases become discharged from tissues into plasma, to complex pathological phenomena. Development of novel testing modalities based on biochemical understanding will aid in the early detecting of certain thrombotic tendencies, as well as in the diagnosis of hereditary and acquired bleeding disorders. Also, molecular studies of abnormal conditions in Nature provide unusual opportunities for validating and extending our knowledge into important regulatory aspects of the physiology of normal blood coagulation.
Specific aims are grouped under the following categories, each representing several different projects. 1. Maturation of factor XIII in the full-term and premature newborn. Is there a fetal form of factor XIII? 2. Molecular studies on hemorrhagic disorders of fibrin stabilization: (a) hereditary deficiencies; (b) target specificities of circulating inhibitors. 3. Novel testing modalities for factor XIII and for tissue transglutaminases, should the latter become discharge into plasma under pathological circumstances. Detection of circulating factor XIIIa activity as an indicator of thrombotic tendency. 4. Fibronectin as the carrier of tissue transglutaminase in plasma. Practical and fundamental considerations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL016346-30
Application #
6125711
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1993-12-05
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
30
Fiscal Year
2000
Total Cost
$203,282
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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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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