Maintenance of healthy and functional neuronal populations is critical for human health. Our lab uses the elegant and powerful model system C. elegans to decipher molecular mechanisms of neuronal function and dysfunction. The biological problems we investigate include touch sensation, neuronal degeneration and aging.
Mechanotransduction--Touch and Feeling at the Molecular Level.
One of the looming mysteries in signal transduction today is the question of how mechanical signals, such as pressure or force delivered to a cell, are interpreted to direct biological responses. A long-standing problem in the mechanotransduction field has been that genes encoding mechanically-gated channels eluded cloning efforts, resulting in a large gap in our understanding of their function. We have identified a new family of ion channels (the degenerin channels) that are hypothesized to normally function as the central mediators of touch transduction and proprioception (how the body maintains coordinated movement) in C. elegans. We are currently combining genetic, molecular and electrophysiological approaches to determine and compare the composition/regulation of mechanosensitive complexes in an effort to contribute to the understanding of the function of this newly discovered channel class.
Molecular Mechanisms of Neurodegenerative Cell Death.
Various cellular insults, including hyperactivation of ion channels, expression of human b-amyloid protein implicated in Alzheimer's disease, and constitutive activation of certain G proteins can induce a necrotic-like cell death in C. elegans. This suggests that diverse initiating stimuli may induce a common death mechanism in injured cells.We are genetically and molecularly deciphering the C. elegans necrotic death mechanism. Toward this end we have identified several novel genes that are required for necrotic-like cell death. We are currently cloning these genes and determining role in necrosis. Elucidation of the molecular bases of necrotic-like cell death in simple animal models should provide insight into the basic biology of inappropriate neuronal death and facilitate the characterization of mechanisms underlying degeneration in human disorders.
Molecular Mechanisms of C. elegans aging.
Several genes that mutate to significantly extend lifespan have been identified in C. elegans, yet little is known about how the animal ages. We have been using cellular markers to study what happens to individual cell types as C. elegans ages. We have found that the nervous system does not dramatically age or degenerate, but muscle deteriorates significantly-a condition similar to human sarcopenia, the progressive muscle loss that accompanies aging. We are dissecting molecular mechanisms of muscle decline using the powerful C. elegans model system.