The long-term objective of the proposed work is to understand mechanisms of mechanotransduction. The ability to detect mechanical energy is essential for our senses of touch, hearing, and balance as well as for on-going regulation of posture, osmotic balance, and blood pressure. In recent years, classical and forward genetic approaches in nematodes, fruit flies, zebra fish, and mice have yielded a small, but expanding list of proteins needed for touch and hearing. However, it is not clear whether or not all of these proteins function in sensory mechanotransduction or, if so, how they might act in concert to convert mechanical energy into electrical signals in neurons. We propose to investigate the molecular physiology of touch-sensitive neurons in the nematode Caenorhabditis elegans. For several reasons, C. elegans is a nearly ideal animal for this research. Now, extensive collections of touch-insensitive mutants, powerful molecular-genetic tools, and an unparalleled description of nervous system anatomy, co-exist with the ability to record electrical signals from single, identified mechanosensory neurons. Newly discovered parallels in the physiology of C. elegans vertebrate touch-sensitive neurons significantly increase the value of C. elegans as a model system. In this proposal, we focus on two classes of mechanosensory neurons (nonciliated PLM neurons and ciliated ASH neurons). Electrophysiological recordings will be made from PLM and ASH in normal animals to determine how mechanotransduction differs in these distinct classes of mechanosensory cells (Aims #1A, 3A). We will determine the cellular function of proteins predicted to form sensory transduction channels and voltage-gated K channels by comparing sensory responses in wild type and mutant cells (AIMS 1A, 3B, & 3C). To investigate how cellular architecture contributes to force transfer, we will also record from mutant animals with defects in extracellular and intracellular structures (Aim 1B). Finally, we will express channels needed for PLM function in heterologous cells and determine how known accessory proteins regulate single channel activity (Aim 2). What is learned from these studies will clarify basic mechanisms of mechanotransduction and could improve the diagnosis and treatment of sensory neuropathies associated with both inherited and acquired diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047715-02
Application #
6914157
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Babcock, Debra J
Project Start
2004-07-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$363,424
Indirect Cost
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Mazzochette, E A; Nekimken, A L; Loizeau, F et al. (2018) The tactile receptive fields of freely moving Caenorhabditis elegans nematodes. Integr Biol (Camb) 10:450-463
Kubanek, Jan; Shukla, Poojan; Das, Alakananda et al. (2018) Ultrasound Elicits Behavioral Responses through Mechanical Effects on Neurons and Ion Channels in a Simple Nervous System. J Neurosci 38:3081-3091
Goodman, Miriam B; Sengupta, Piali (2018) The extraordinary AFD thermosensor of C. elegans. Pflugers Arch 470:839-849
Krieg, Michael; St├╝hmer, Jan; Cueva, Juan G et al. (2017) Genetic defects in ?-spectrin and tau sensitize C. elegans axons to movement-induced damage via torque-tension coupling. Elife 6:
Nekimken, Adam L; Mazzochette, Eileen A; Goodman, Miriam B et al. (2017) Forces applied during classical touch assays for Caenorhabditis elegans. PLoS One 12:e0178080
Nekimken, Adam L; Fehlauer, Holger; Kim, Anna A et al. (2017) Pneumatic stimulation of C. elegans mechanoreceptor neurons in a microfluidic trap. Lab Chip 17:1116-1127
Glauser, Dominique A; Goodman, Miriam B (2016) Molecules empowering animals to sense and respond to temperature in changing environments. Curr Opin Neurobiol 41:92-98
Lockhead, Dean; Schwarz, Erich M; O'Hagan, Robert et al. (2016) The tubulin repertoire of C. elegans sensory neurons and its context-dependent role in process outgrowth. Mol Biol Cell :

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