Olfactory transduction is the process by which olfactory sensory neurons (OSNs) transform odor information into neuronal electrical signals. Over the past two and a half decades, extensive investigations have led to the elucidation of a core transduction pathway in vertebrate OSNs. However, the processes that regulate transduction to allow for proper sensitivity and response kinetics are not well understood. Calcium is a key olfactory transduction regulator. Calcium enters the sensory cilium through the olfactory cyclic nucleotide-gated (CNG) channel during the odor response, amplifies OSN depolarization, and also negatively regulating several olfactory transduction components. This negative regulation governs OSN adaptation--a phenomenon manifested as reduced sensitivity upon sustained or repeated stimulation. In this proposal, we propose to take advantage of multiple genetically modified mouse strains that we generated to: 1) investigate the integration of multiple Ca2+-dependent feedback mechanisms in OSN adaptation (Aim 1);and 2) investigate the role of negative regulatory mechanisms, which function in termination and adaptation, in setting OSN sensitivity at rest (Aim 2). Electrophysiological analysis, at the level of intact olfactory epithelium and the isolated single cell level, will be conducted on mice carrying double or triple mutations for calcium-dependent feedback mechanisms (Aim 1) as well as on mice that lack a calcium-dependent feedback mechanism and also lack efficient calcium extrusion (Aim 2). The long-term goal of this proposal is to elucidate the molecular mechanisms underlying olfaction. The proposed investigation will lead to a better understanding of how OSNs encode the intensity and temporal features of odor stimulations by regulating sensitivity and response kinetics. The knowledge gained from the proposed research will enhance our understanding of normal olfactory function and olfactory dysfunctions.

Public Health Relevance

The sense of smell is important for locating food, mates, avoiding danger, and enhancing the quality of life. Despite the fact that many of the molecular components that allow us to smell are known, the mechanisms governing the sensitivity and response speed are not well understood. The proposed research will enhance our understanding of the basic responses of the olfactory system, which will give us insight into the genetic and physiological causes of smell disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007395-07
Application #
8575538
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2005-04-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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