The exquisite sensitivity and discrimination capabilities of mammalian olfaction arise from a combination of novel genetic regulatory mechanisms, cellular specializations, and the overall anatomy and architecture of the olfactory system. One of the key aspects of genetic control is the selective expression of one allele of a single olfactory receptor (OR) gene in each sensory neuron. Past research in this area has demonstrated this one-receptor one-neuron principle and revealed an important role for the olfactory receptor protein for feedback that establishes and maintains this relationship. A molecular understanding of processes underlying this regulation has been hampered by the complexity and effort required to examine these process in genetically modified animals. Experiments in transgenic mice by several investigators, including our own, have suggested an additional critical role for the receptor coding sequence in determining the transcription state of the receptor. In this grant we will use molecular and genetic approaches to elucidate mechanisms responsible for the remarkable regulation of OR expression. We will test the hypothesis that nucleic acid sequences within the protein coding regions of ORs control functional expression at the genomic, transcriptional or translational level and that this activityis important for proper OR expression.
In specific aim 1, we utilize a cell culture model to investigate and understand mechanistically one aspect of OR expression. In parallel, we propose to determine the sequences within the OR coding sequence that are responsible for this unusual regulatory process.
In specific aim 2, we will utilize genetically modified mice to examine the consequences of altering this regulation in vivo. Together, these experiments may reveal new mechanisms of gene regulation. The proposed research will incorporate novel expression systems and a broad array of molecular methods to systematically study a regulatory process that is likely to be shared by other biological systems Elucidating these mechanisms may provide additional insight in genes that play critical roles in human health and disease.

Public Health Relevance

The mammalian olfactory neuron performs one of the most complex regulatory programs in biology. It must select a single odorant receptor gene from the more than one thousand that are distributed across the entire genome and express only one of the two gene copies of a particular receptor in any one cell. Furthermore, it must ensure that no additional receptor genes are subsequently expressed in that cell. This proposal seeks to model this process in a simple cell culture system and elucidate the molecular mechanisms responsible for this exquisite control. It is likely that these mechanisms will be shared by many additional complex regulatory pathways that play critical roles in human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DC008295-06A1
Application #
8801138
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2006-07-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Chen, Mengfei; Reed, Randall R; Lane, Andrew P (2017) Acute inflammation regulates neuroregeneration through the NF-?B pathway in olfactory epithelium. Proc Natl Acad Sci U S A 114:8089-8094