| Current
Research For a list of our past and
current publications, click
here.
Our 2008-2009 agenda highlights
the following themes:
I. Role of the α7β1 Integrin as a Mechanotransducer that Regulates Intracellular Signaling
Objective |
The α7β1 integrin is
a heterodimeric transmembrane receptor that links the
extracellular matrix (ECM) on the outside of muscle fibers to
the actin cytoskeleton on the inside of muscle fiber. In
addition to providing the fundamental basis of adhesion,
integrins regulate the mechanotransduction of cellular
signaling. The integrin can transform mechanical force into
chemical signals which result in cellular and molecular
adaptations necessary for increased muscle growth and integrity.
Our laboratory has found that exercise-induced mechanical
loading can increase α7 integrin RNA (Boppart, submitted) and
protein and that overexpression of the α7 integrin inhibits
strain-induced c-jun NH2 terminal kinase (JNK) activity
(Boppart, Am J Physiol, 2006). Since JNK is associated with
muscle injury and insulin resistance, α7 integrin-mediated
inhibition of JNK may provide physiological and metabolic
advantages to skeletal muscle.
Our laboratory currently utilizes several lines of genetically
modified mice and primary cell lines to examine the role of the
integrin in altering the intracellular molecular response to
exercise and mechanical strain, particularly molecules known to
induce growth or increase protection against injury (MAPK’s,
insulin/IGF signaling pathways).
II. Role of the α7β1 Integrin as a Recruitment Tool for Adult Stem Cells
Objective |
Stem cells other than satellite cells have been recently
identified in skeletal muscle that can contribute to repair
following injury or disease. However, these cells are limited in
their abundance and ability to contribute to skeletal muscle,
and thus, current research is focused on identifying molecules
or techniques that can increase recruitment of these cells to
muscle. Methods that exploit endogenous molecular mechanisms for
increased recruitment of regenerative stem cells are especially
advantageous since they can bypass graft vs. host interactions
associated with myoblast or stem cell transplantation.
Our current research is focused understanding the relationship
between the integrin, mechanical loading, and increased stem
cell recruitment to skeletal muscle for enhanced regeneration
and protection from muscle wasting.
III.
Role of the α7β1 Integrin in the Prevention of Muscle Wasting Disease, Including Sarcopenia, Muscular
Dystrophy, and Cancer Cachexia
Objective |
The α7β1 integrin is a critical transmembrane linkage protein in
skeletal muscle that has been shown to ameliorate disease
symptoms and extend longevity in mice with a severe form of
muscular dystrophy (Burkin, J Cell Biol, 2001).
Although the α7 integrin can restore muscle function by
increasing adhesion and stabilization of myotendinous and
neuromuscular junctions, the precise molecular mechanism by
which this integrin can increase muscle integrity is obscure.
Our investigations in mouse models of sarcopenia and other
muscle wasting diseases will direct us toward optimal use of the
α7 integrin for therapy and increasing the quality of life for
those suffering from debilitating muscle wasting conditions.
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