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Molecular Glue has Therapeutic Future - National I
N A T I 0 N A L I N S T I T U T E S 0 F H E A L T H
National Institute of General Medical Sciences
Research Reports
September 1993
Editor: Doris Brody
(301) 496-7301
Research Reports, a feature service by the Office of Research
Reports of the National Institute of General Medical Sciences, is
designed to let you know what some of our grantees are doing.
This issue contains a list of a number of recent NIGMS grant
awards and the following stories:
Molecular Glue Has Therapeutic Future
New techniques now permit scientists to study the molecular
basis for cell adhesion in tissues and organs. Methods for
increasing or decreasing cell stickiness have a host of
therapeutic and commercial possibilities that biotechnology
companies are eager to develop.
Molecular Glue Has Therapeutic Future
What holds cells together in tissues and organs? Although
it is clear that cells must stick together to sustain life in
multicellular organisms, until recently little was known about
the molecular mechanisms of cell adhesion. In the last few
years, improved techniques have enabled researchers to begin to
isolate and study cell adhesion molecules (called CAM'S) and to
obtain specific answers to the question of how cells hold
together.
Both the new understanding of CAM's and the techniques that
made their discovery and further study possible are the results
of basic research, such as that supported by the National
Institute of General Medical Sciences (NIGMS), on the fundamental
properties of living cells. This research has opened the door to
many exciting therapeutic possibilities.
Although much remains to be discovered about the complex
mechanisms of cell adhesion, biotechnology firms are already
rushing to use the new information to develop treatments for
disorders as diverse as impaired wound healing, cancer, multiple
sclerosis, rheumatoid arthritis, osteoporosis, atherosclerosis,
and bacterial and viral infections. All of these approaches are
based on methods that enhance or interfere with the molecules
responsible for the basic "stickiness" of cells.
Scientists have long known that something in the cells of
primitive animals like sponges causes the cells to recognize each
other and to stick together. Experiments, the first of which
were conducted as long ago as 1907, showed that a mass of gently
sieved sponge tissue will spontaneously reassemble into an
organism similar in form to the original sponge. When sieved
together, different species of sponges will find cells of their
own species before reassembling.
The specific molecules involved in cell adhesion are located
both in the membranes of cells and in the so-called extracellular
matrix that lies between cells. These molecules have been
relatively difficult to study because many membrane proteins can
be isolated only by agents that destroy the membrane and render
the proteins very difficult to purify. Often, the reagents used
in laboratories also unfold proteins, destroying their chemical
properties. Partly because of these technical difficulties,
for many years, biologists paid little attention to the
relationship between the extracellular matrix and cell membranes.
Basic biology texts described the function of the extracellular
matrix as largely connective and structural.
Today, scientists know there are at least four major
families of protein receptors that act as go-betweens to permit
cell adhesion to take place. Each of these families--the
cadherins, immunoglobulins, selecting, and integrins--is the
focus for the development of new therapeutic products. The
different cell adhesion receptors interact with extracellular
matrix proteins like fibronectin and laminin and with
intracellular proteins, especially those involved in cell
structure.
The first integrins were discovered in 1982 by NIGMS
grantee Alan F. Horwitz, Ph.D., now at the University of Illinois
in Urbana-Champaign, and Clayton Buck at the Wistar Institute in
Philadelphia, Pennsylvania. They found that these receptors
span the cell membrane and link the extracellular matrix with
the internal cell skeleton.
Much progress has been made since then in understanding
integrins and in the development of tools for studying them.
Dr. Horwitz has characterized the structure of integrin
components and defined the binding of integrins to extracellular
and intracellular molecules. He has also developed a genetic
system for the expression and functional analysis of mutant
integrins, and has used it to map functional regions in the
molecules. Recently, he identified intracellular complexes that
interact with integrins and that may be involved in
integrin-mediated signal transduction.
Evidence that integrins mediate transmembrane signals is of
major importance, because it provides an explanation for how the
adhesion of one cell to another cell or to the surrounding
environment can trigger division, differentiation, activation,
and movement. These processes are essential in fertilization,
embryonic development, and the maintenance of tissues.
NIGMS has also supported, through its trauma and burn
injury research program, the development of a cell adhesion-based
experimental product to speed wound healing. Of all the
proposed new treatments based on cell adhesion research, this
product, called Telio-Derm, is among the closest to actual
marketing. Telio-Derm is designed to treat the slow healing or
lack of healing in wounds such as diabetic ulcers and severe
burns. Poor wound healing is a serious medical problem in this
country, affecting millions of individuals and causing severe
pain or death in many patients.
Telio-Derm is a gel that holds a synthetic molecule
containing the three amino acids that form the cell attachment
site of many extracellular matrix proteins--a site that is
recognized by integrins. The gel is designed to speed wound
repair by providing an "anchor" for skin cells moving into the
wound bed.
The next few years are likely to yield continued growth in
understanding of the science of cell adhesion as well as rapid
growth in the clinical uses of this understanding.
Doris Brody
Recent NIGMS Grant Awards
This sampling of titles from the more than 3,000 grant
awards NIGMS makes each year is designed to give you an idea of
the basic research the Institute supports. A computer printout
of all current (new and continuing) NIGMS grants at your
institution is available from us, if you request it. Among the
awards that were made in late 1992 are the following:
Bowman Gray School of Medicine
H. Alexander Claiborne, Jr.: "Mechanisms Involved in Flavin-
linked Oxygen Metabolism"
Health Science Center at Syracuse
David R. Mitchell: "Molecular and Genetic Analysis of Flagellar
Dyneins"
Iowa State University of Science and Technology
Jack Horowitz: "Transfer Ribonucleic Acid Structure and Function"
Kansas State University
Michael R. Kanost: "Serine Proteinase Inhibitors in Insects"
Medical College of Wisconsin
Kalpana Chakraburty: "Regulation of Ribosomal Reactions"
Michigan state University
John R. Stille: "Selective Intramolecular Carbon-Carbon Bond
Formation"
New York University
Gloria M. Coruzzi: "Regulation of Amino Acid Biosynthesis Genes
in Plants"
Ohio State University
Berl R. Oakley: "Molecular Biology of Microtubule-Interacting
Proteins"
Pennsylvania State University--University Park
Kenneth A. Johnson: "Mechanism and Fidelity of DNA Replication"
Rice University
John S. Olson: "Functional Properties of Hemoglobins and
Myoglobins"
Sloan-Kettering Institute for Cancer Research
Stewart H. Shuman: "Vaccinia Virus DNA Topoisomerase I"
State University of New York, Stony Brook
Charles H. Lang: "Mechanisms of Insulin Resistance in sepsis"
Syracuse University
Joan Maddox Belote: "Molecular Study of a Sex Transformer Gene in
Drosophilall
Texas A & M University, College Station
Frank M. Raushel: "Isotopic Probes of Enzymatic Reaction
Mechanisms"
University of California, Irvine
Francisco J. Ayala: "Evolutionary Genetics of a Model System"
University of California, Santa Barbara
Jacob N. Israelachvili: "Structure and Interactions of Model
Biomembranes"
University of Chicago
William D. Wulff: "Synthetic Applications of Carbene Complexes"
University of Colorado at Boulder
Susan K. Dutcher: "Genetic Analysis of Basal Body Function"
University of Florida
Philip J. Laipis: "Genetic Analysis of Mammalian Mitochondrial
Inheritance"
University of Houston
William R. Widger: "Genomic Organization of Photosynthetic Genes"
University of Iowa
Chi-Lien Cheng: "Transcriptional Control of Arabidopsis Nitrate
Reductasell
University of Maryland, Baltimore
Daniel N. Darlington: "Death and Shock from Adrenal
Insufficiency"
University of Michigan
C.H. Williams, Jr.: "Structure and Mechanism of Flavoenzymes"
University of Minnesota
Lawrence Que, Jr.: "Non-Heme Iron Oxygen Activation in Enzymes
and Models"
University of Mississippi medical center
Mona T. Norcum: "Structure of Aminoacyl-tRNA Synthetase
Complexes"
University of Missouri, Columbia
John F. Cannon: "Type 1 Protein Phosphatase of S. cerevisiaell
University of Nebraska, Lincoln
Carolyn M. Price: "Telomere Structure in Euplotes crassus"
University of Notre Dame
Robert W. Scheidt: "X-Ray and Chemical Studies of
Metalloporphyrins"
University of Pittsburgh
Robert A. Branch: "Mechanisms of Amphotericin B Nephrotoxicity"
University of Rhode Island
Ching-Shih Chen: "Metabolic Stereoisomeric Inversion of Chiral
Drugs"
University of Southern California
Roger F. Duncan: "Heat Stress Effects on Protein Synthesis"
University of Tennessee at Memphis
Lawrence M. Pfeffer: "Interferon Action on Cell Structure and
Proliferation"
University of Texas at Austin Stephen F. Martin: "Design and
Synthesis of Novel Pseudopeptides"
University of Vermont & State Agricultural College
Douglas J. Taatjes: "Subcompartmentation of Golgi Apparatus
Glycosylation"
University of Wisconsin, Madison
Patricia J. Kiley: "Regulation of Gene Expression by Oxygen"
Vanderbilt University
Roger J. Colbran: "Regulation of Calmodulin-Dependent Protein
Kinase III'
Virginia Commonweadth University
Mark S. Rosenkrantz: "Control of Citrate Synthase Expression in
Yeast"
Washington State University
Bruce A. McFadden: "Biochemistry of Membrane and Catalytic
Proteins"
Washington University
Elliot L. Elson: "Biophysical Studies of Cytoskeletal Function"
Yale University
Nancy Maizels: "Molecular Mechanisms of Isotype Switch
Recombination"
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