Rice University logo
 
Top blue bar image
Investigating the molecular processes that link hemostasis-thrombosis and inflammation
 

Research

For over 25 years, the Moake Laboratory in Hematological Research has investigated the basic mechanisms of hemostasis-thrombosis under flowing conditions, and the pathophysiology of thrombotic microangiopathies. More specifically this has included:

  • Shear stress-induced, von Willebrand factor (VWF)-mediated platelet clumping;
  • Pathophysiology and therapy of thrombotic thrombocytopenic purpura (TTP), and hemolytic-uremic syndromes HUS), and other types of thrombotic microangiopathies; and
  • Molecular interactions between VWF and complement.

The laboratory team was first to discover that:

  • Unusually large VWF (ULVWF) multimers secreted from endothelial cells are not processed properly, and cause systemic platelet aggregation, in TTP (1982; publication # 1 on publications page);
  • High shear stress-induced platelet aggregation requires large VWF multimers, (1986; publication # 3 on publications page);
  • Inhibition of the VWF-cleaving protease, ADAMTS-13, by Shiga-like toxin from Escherichia coli contributes to ULVWF-mediated thrombosis in the microcirculation of the kidney in the common diarrhea-associated type of HUS (2005 and 2013; publications # 11 and 16 on publications page);
  • The alternative complement pathway is initiated and amplified by complement component C3 binding to ULVWF multimers secreted by, and anchored to, human endothelial cells (2013; publication # 19 on publications page), providing a molecular linkage between hemostasis-thrombosis and inflammation; and
  • Factor H, a regulatory protein in the alternative complement pathway, also has reductase activity for soluble VWF multimers (2013; publication # 17 on publications page).

Current laboratory emphasis

New research in the Moake laboratory looks at molecular interactions between the earliest events in hemostasis-thrombosis (VWF) and inflammation (alternative complement pathway).

VWF multimeric strings_web

 

 

 

 

 

 

 

 

(Above) Histamine-stimulated HUVECs
secrete and anchor ultra-large (UL)
VWF multimeric strings
(green; image = 60X).

HUVEC_web

 

 

 

 

 

(Above) Human umbilical vein endothelial
cells (HUVECs) synthesizes and contain
the VWF-containing protease, ADAMTS-13
(red; immunofluorescent image = 60X).

 Alternative Complement_web  Alternative Complement2_web

Above) Alternative complement pathway
components are assembled and
activated on endothelial cell –secreted/
anchored ULVWF multimeric strings.

(Above) Complement component C3,
but not C4 from the classical or lectin
pathways, binds to endothlial cell-
secreted/anchored ULVWF multi-
meric strings.
~
 Shiga-like toxin_web (Image Left) Shiga-like toxin (Stx0 produced
by enterohemorrhagic E. coli, impairs
ADAMTS-13 cleavage of VWF in the diarrhea-
associated hemolytic-uremic syndrome.
VWF stored_web (Image Left) VWF is stored in endothelial cell
Weibel-Palade bodies (green) after synthesis,
whereas the complement regulatory protein
factor H 9 (red), is not stored in an organelle
after synthesis (image = 100X).