Project Details
Description
DESCRIPTION: Mechanical forces such as focused pressure or membrane stretch
play central, but poorly understood, roles in biology. What types of
molecules mediate mechanical signaling? Elegant electrophysiological
studies have implicated a class of mechanically-gated ion channels in
mechanotransduction. A recent breakthrough in this field is that analyses
of C. elegans have identified members of a family of eukaryotic ion channels
postulated to play central roles in mechanical signaling. In specialized
touch sensory neurons, MEC-4 and MEC-10 channel subunits mediate touch
transduction. A related subunit, UNC-8, modulates locomotion and is
proposed to be involved in nematode proprioception (how an organism
maintains a sense of where its different parts are and coordinates their
motions).
The identification of candidate mechanically-gated channels in C. elegans
has now laid the groundwork for deciphering molecular mechanisms of
mechanical signaling. Here the principal investigator proposes to combine
genetic, molecular and biochemical approaches to deduce the molecular
compositions and identify regulators of two mechanosensitive complexes. The
specific goals are: 1) to test and extend models of channel/cytoskeleton
interaction by defining protein interactions mediated by MEC-4 and MEC-10
intracellular domains; 2) to characterize the UNC-8 candidate proprioception
channel by identification of subcellular localization, cellular site of
action, and additional channel subunits; and 3) to clone and characterize 4
identified loci that genetically interact with unc-8 and to deduce the
mechanisms by which they influence UNC-8 channel function.
This work will test, refine and extend working models for molecular
mechanisms of mechanotransduction, a significant issue because so little is
understood of mechanical signaling and so many biological processes (ranging
from cell volume regulation to the senses of touch, hearing and balance)
depend upon it. In addition, the MEC-4/MEC-10 and UNC-8 channels are
related to human ENaC channels that mediate Na+ readsorption and are
essential for maintenance of electrolyte balance, blood pressure regulation,
and clearing of fluid from neonatal lungs. Analyses of nematode and
mammalian channels to date indicates that they work in fundamentally similar
ways and thus data we generate in this work from a unique experimental
perspective are expected to provide similar insight into general working of
the channel class and hold implications for betterment of human health.
Status | Finished |
---|---|
Effective start/end date | 9/8/98 → 8/31/03 |
Funding
- National Institute of Neurological Disorders and Stroke: $215,615.00
- National Institute of Neurological Disorders and Stroke: $210,089.00
ASJC
- Molecular Biology
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