Abstract

The long-term goal of this research is to elucidate molecular mechanisms underlying sensory perception. Specifically, we seek in this proposal to understand how Ca2+ feedback mechanisms regulate olfactory sensory neuron (OSN) function in vivo and how these mechanisms contribute to the ability of the animal to detect and discriminate odors. Ca2+ plays a central role in regulating OSN responses by modulating several signal transduction proteins via calmodulin (CaM). Previous in vitro studies have implicated the olfactory cyclic nucleotide-gated (CNG) channel and phosphodiesterase 1C (PDE1C) as major targets of Ca2+/CaM. However, the functional significance of these Ca2+/CaM-target interactions in OSN physiology and olfactory behavior has not been determined. We are employing molecular genetics to specifically eliminate Ca2+/CaM binding sites in the CNG channel and PDE1C. This approach allows a systematic analysis of the role of Ca2+/CaM in regulating OSN physiology, and ultimately olfactory behavior.
In Specific Aim 1 we will determine the contribution of individual CaM-binding domains of the CNG channel to Ca2+/CaM regulation of OSN responses.
Specific Aim 2 seeks to delineate how the basal activity and Ca2+/CaM-stimulated activity of PDE1C independently regulate OSN responses.
In Specific Aim 3, we will investigate how regulation of OSN physiology aids olfactory behaviors such as odor tracking and discrimination. The proposed experiments will lead to a better understanding of the connection from regulation of signal transduction proteins to OSN physiology, and to olfactory behavior. This knowledge will further our understanding of normal olfactory function and olfactory dysfunctions, and will provide insight into principles common to all sensory systems.
This research aims to understand how regulation of key proteins in the odor-detecting cells influences the sense of smell. The knowledge from these studies will add to our understanding of both the normal function of the olfactory system and olfactory dysfunctions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007395-04
Application #
8012808
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2008-02-27
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$361,769
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Dong, Frederick N; Amiri-Yekta, Amir; Martinez, Guillaume et al. (2018) Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse. Am J Hum Genet 102:636-648
Chew, Kylie S; Renna, Jordan M; McNeill, David S et al. (2017) A subset of ipRGCs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice. Elife 6:
Gigante, Crystal M; Dibattista, Michele; Dong, Frederick N et al. (2017) Lamin B1 is required for mature neuron-specific gene expression during olfactory sensory neuron differentiation. Nat Commun 8:15098
Chew, Kylie S; Fernandez, Diego C; Hattar, Samer et al. (2017) Anatomical and Behavioral Investigation of C1ql3 in the Mouse Suprachiasmatic Nucleus. J Biol Rhythms 32:222-236
Vinberg, Frans; Wang, Tian; De Maria, Alicia et al. (2017) The Na+/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision. Elife 6:
Ferguson, Christopher H; Zhao, Haiqing (2017) Simultaneous Loss of NCKX4 and CNG Channel Desensitization Impairs Olfactory Sensitivity. J Neurosci 37:110-119
Talaga, Anna K; Dong, Frederick N; Reisert, Johannes et al. (2017) Cilia- and Flagella-Associated Protein 69 Regulates Olfactory Transduction Kinetics in Mice. J Neurosci 37:5699-5710
Chen, Chih-Ming; Orefice, Lauren L; Chiu, Shu-Ling et al. (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci U S A 114:E619-E628
Ye, Hong; Wang, Xiaofang; Sussman, Caroline R et al. (2016) Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies. J Am Soc Nephrol 27:1312-20
Cai, Yujun; Nagel, David J; Zhou, Qian et al. (2015) Role of cAMP-phosphodiesterase 1C signaling in regulating growth factor receptor stability, vascular smooth muscle cell growth, migration, and neointimal hyperplasia. Circ Res 116:1120-32

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