This proposal involves the molecular and functional characterization of a human dysfibrinogen. Fibrinogen is a key component of the clotting cascade. Knowledge of the structure and function of variant fibrinogens can benefit researchers and clinicians alike by increasing understanding of abnormal hemostasis, in this study, a dysfibrinogen present in two siblings will be analyzed in terms of its genotypic and phenotypic characteristics. First, the fibrinogen genes will be sequenced to identify the mutation(s) at the DNA level. Preliminary data show the presence of a point mutation in the codon for amino acid 383 of the gamma chain. This mutation, a serine instead of a threonine, is hypothesized to be responsible for functional changes in the expressed protein. Second, recombinant forms of fibrinogen encompassing each mutation will be synthesized by transfection into a baby hamster kidney cell line. Third, analysis of fibrinogen function will be performed on both the recombinant forms and on plasma-derived fibrinogen. Fibrinopeptide cleavage, fibrin polymerization, factor Xllla cross-linking, and plasmin mediated fibrinolysis will be assessed. Scanning electron microscopy will be used to visualize the actual clot formed. This study will provide valuable information about the structural and functional behavior of this dysfibrinogen and will ultimately improve understanding of clot formation and the process of hemostasis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL076085-01A1
Application #
6836282
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Mondoro, Traci
Project Start
2004-08-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$52,492
Indirect Cost
Name
Oregon Health and Science University
Department
Pathology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Flood, Veronica H; Al-Mondhiry, Hamid A; Rein, Chantelle M et al. (2008) Fibrinogen Hershey IV: a novel dysfibrinogen with a gammaV411I mutation in the integrin alpha(IIb)beta(3) binding site. Thromb Haemost 99:1008-12
Flood, Veronica H; Nagaswami, Chandrasekaran; Chernysh, Irina N et al. (2007) Incorporation of fibrin molecules containing fibrinopeptide A alters clot ultrastructure and decreases permeability. Br J Haematol 138:117-24
Flood, Veronica H; Al-Mondhiry, Hamid A; Farrell, David H (2006) The fibrinogen Aalpha R16C mutation results in fibrinolytic resistance. Br J Haematol 134:220-6