In Vivo Sickle Cell Vasoocclusion: Adhesion Mechanisms

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):
The overall objective of this proposal is to understand the adhesive
mechanisms mediating vaso-occlusion in sickle cell disease. Although
several studies have documented roles for a number of adhesion molecules
in sickle cell adhesion in vitro, there is very little in vivo data.
The recent development of a mouse strain that exclusively expresses
human globins provides us with the opportunity to study the adhesive
mechanisms in vivo using intravital microscopy. Our preliminary studies
indicate that cytokine-induced inflammation produces severe
vasoocclusion in post-capillary venules in the cremaster muscle of
sickle cell mice. Our results indicate that adherent leukocytes play a
key role in this process since they can bind circulating sickle cell
erythrocytes (SS RBCs) and initiate venular occlusion. Endothelial
selectin-deficient mice, which display defects in leukocyte recruitment
in venules, show few SS RBC-leukocyte interactions and no vasooclusion.
In this proposal, we wish to further investigate the hypothesis that
vasooclusion in sickle cell disease is initiated by the adhesive
interaction between SS RBCs and adherent leukocytes. In specific aim I,
we will identify the type of leukocyte (mononuclear vs
polymorphonuclear) that interacts with SS RBCs in vivo, and we will
further evaluate the roles of leukocyte and endothelial adhesion
molecules in vasoocclusion using adhesion molecule knockout mice and
inhibitory antibodies; we will also develop a model to investigate
vasoocclusion in the bone marrow microvasculature, an important target
in sickle cell disease. In specific aim II, we will develop adhesion
assays to dissect the molecular mechanisms mediating SS RBC-leukocyte
interactions and, in parallel, we will conduct intravital experiments to
confirm putative adhesion pathways. In specific aim III, we propose to
evaluate the in vivo functions of three adhesion molecules previously
shown to participate in sickle cell adhesion (von Willebrand factor,
beta3 integrins and thrombospondin), using adhesion molecule knockout
mice and sickle cell animals. The proposed studies should shed new
light on the in vivo mechanisms of sickle cell vasoocclusion and may
lead to novel ways to treat sickle cell crises and other complications
of this disease.
StatusFinished
Effective start/end date9/30/017/31/02

Funding

  • National Heart, Lung, and Blood Institute: $423,750.00

ASJC

  • Molecular Medicine
  • Hematology
  • Cell Biology
  • Immunology
  • Developmental Biology

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.