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MERIT Award Recipient: Timothy A. Springer, Ph.D.

Timothy A. Springer       Sponsoring NCI Division:Division of Cancer Biology (DCB)
Grant Number:R37CA031798
Award Approved:February 2004
Institution:Immune Disease Institute, Harvard University
Department:Pathology
Timothy A. Springer, Ph.D.
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Lymphocyte Function Associated Antigens

Adhesion molecules are a class of cell surface proteins that function in the interactions of immune system cells (leukocytes) with other cells. Dr. Timothy Springer and his colleagues initially identified and began to characterize adhesion molecules in the early 1980s. These molecules include the integrin LFA-1, which integrates the extracellular environment with the environment inside cells, including the cytoskeleton and signaling molecules. These molecules also include intercellular adhesion molecules (ICAMs), which act as binding partners (ligands) for LFA-1 and are increased in inflammatory and autoimmune diseases. The importance of integrins on leukocytes is illustrated by an inherited disease in which integrins are deficient, termed leukocyte adhesion deficiency (LAD). In LAD patients, leukocytes are present in the blood circulation in large numbers, but fail to exit the blood to migrate to sites where they are needed to fight infection. This deficit in migration was one of the first clues that these molecules are not only important in antigen-specific immune responses, but also function in trafficking of leukocytes from the bloodstream into inflamed tissues, and in patrolling of the body by immune lymphocytes for signs of infection.

More recently, advances in the understanding of the structure of integrins and ICAMs have enabled a broadening and deepening in Dr. Springer's research efforts to understand how the functions of LFA-1 and ICAMs are regulated at the molecular level and to understand the molecular basis of integrin antagonism by antibodies and small molecules that might someday be developed into drugs. Dr. Springer and his colleagues are investigating how LFA-1 transmits signals bidirectionally across the cell membrane to regulate both binding to extracellular ligands and activation of intracellular signaling pathways.

Targets of their studies include the conformational changes in both the extracellular and intracellular domains of the molecules, and the mechanisms that allow them to be coupled by signals across the cell membrane. The Springer lab will determine the mechanism of transmission of conformational change from one domain to another in the extracellular domain portion of LFA-1 using a number of complementary experimental strategies: generation of mutations that stabilize particular conformational states or affect inter-domain linkages, characterization of small molecule antagonists with newly defined mechanisms of action, use of antibodies to activation sites on the adhesion molecules, measurement of ligand binding, determination of overall conformational states of LFA-1 by electron microscopy, and determination of ligand binding conformations by crystal structure analysis. They will also investigate the contributions to cellular adhesiveness of molecular clustering in the membrane and of intermediate and high affinity states of LFA-1. These studies will enhance our understanding of how cells of the immune system can be regulated for diverse therapeutic purposes and will build on previous successes of Dr. Springer and his colleagues in developing integrin-directed antibody-based drugs for treatment of the autoimmune disease psoriasis.

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