FUNCTION OF LYMPHOCYTE B1 INTEGRINS

Project: Research project

Description

Integrins play important roles in immune response, lymphocyte targeting,
and regulation of gene expression. Recently, alpha3 and alpha4 chains of
integrins VLA3 and 4 were cloned and sequenced. VLA3 is a fibronectin
(FN)/collagen/laminin receptor. VLA4 is a) a FN receptor, b) receptor for
vascular cell adhesion molecule-1 (VCAM-1) which is expressed on an
activated endothelial cell surface, and c) a homing receptor of lymphocytes
for Peyer's patch. VLA5 is a classical FN receptor which recognizes the
RGD sequence of a FN cell binding domain. Each integrin plays a role in
lymphocyte function, and therefore is a potential diagnostic and
therapeutic target in immunologic diseases. To elucidate the mechanism of VLA3-5/ligands interaction, it is proposed 1)
to identify the VLA3 binding sites in collagen, laminin and FN molecules by
using the recombinant VLA3 expressed in transfected cells and ligand
fragments or synthetic peptides, 2) to identify candidate ligand binding
sites on VLA3-5 molecules by chemical cross-linking of the labeled
synthetic peptides from the identified binding sites in the ligand
molecules (e.g. CS-1 peptide for VLA4, RGD containing peptide for VLA5) to
integrins, and 3) to examine a) the effects of the mutation of the
identified ligand binding sites, b) the effects of the introduction of the
function inhibiting mutations in beta2 or beta3 integrin in patients [e.g.
Glanzmann's thrombasthenia (Asp 119 to Tyr in beta3 chain)] into the
corresponding site of beta1 integrin on the functions of the VLA3-5. In
order to accomplish the proposed work the stably transfected CHO cell lines
which express a large quantity of recombinant VLA3 or VLA4 species on the
surface will be established (VLA5 overproducing cells are already
available). These experiments will analyze the common and specific mechanisms of VLA3-
5/ligand interaction. Peptides which modify these interactions might
modulate the targeting and function of lymphocytes, monocytes and other
cells involved in the pathogenesis of the immunologic diseases.
StatusFinished
Effective start/end date7/1/918/31/06

Funding

  • National Institutes of Health: $237,600.00
  • National Institutes of Health: $296,320.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $283,680.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $237,600.00

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Integrins
Ligands
Fibronectins
Integrin alpha5beta1
Binding Sites
Peptides
Integrin beta Chains
Immune System Diseases
Lymphocytes
CD29 Antigens
CD18 Antigens
Thrombasthenia
Collagen Receptors
Laminin Receptors
Peyer's Patches
Mutation
Vascular Cell Adhesion Molecule-1
CHO Cells
Gene Expression Regulation
Laminin

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)