Allele-specific Expression of a Bitter Taste Receptor
Maneno muhimu
Kikemikali
Maelezo
The Basic Biology of Bitter Taste. The perception of bitter taste is thought to have evolved as a mechanism to protect against the ingestion of toxic materials, and is the result of ligand-activation of one of more than 25 different bitter taste receptors, so-called T2Rs (1). These receptors are found on the tongue in what are called fungiform papillae, mushroom-like structures that contain taste buds with receptors responding to a variety of tastes including sweet, salty, sour, umami, and bitter. A prototypical example of one of these bitter ligands is phenylthiocarbamide (PTC), which actives the T2R38 receptor. While initially identified in type II taste cells, T2R38 is also expressed in nasal epithelium, where it participates in innate immune defense responses to invading bacteria (2-6).
TAS2R38: A Model System for Genotype-Phenotype Studies. Prior studies have identified two main forms of T2R38, active and inactive, which are characterized by three genetic variants in the TAS2R38 gene. These variants result in three amino acid changes, proline (P) to alanine (A) at position 49, alanine (A) to valine (V) at position 262, and valine (V) to isoleucine (I) at position 296 in the T2R38 receptor. Individuals who are homozygous for the active (PAV/PAV) form detect bitterness in compounds containing a thiourea (-N-C=S) moiety, including PTC, 6-n-propylthiouracil (PROP), and the plant compound goitrin, common in foods such as green vegetables (7-9). They also respond to acyl-homoserine lactones (AHLs), a class of compounds produced as signaling molecules by certain bacteria, triggering a rapid defense reaction consisting of increased ciliary beat frequency (CBF) to facilitate mucociliary clearance, and generation of nitric oxide (NO), a gas that can diffuse into the airway and kill bacteria (4). In contrast, those who are homozygous for all three variants (AVI/AVI) consume these compounds without perceiving them as bitter and do not appear to respond to AHLs (10). The frequency of both the active and inactive forms of TAS2R38 is at a near balance of 50:50 in many human racial groups, including Americans of European and African descent.
The Heterozygote Hypothesis. Interestingly, individuals heterozygous for the active form of the receptor (AVI/PAV) exhibit highly variable phenotypes, with some people very sensitive to bitter compounds, and others needing high concentrations to taste them at all (11). While the investigators know that taste papillae density plays at least some role in this variability
, our preliminary taste data suggest that the range of response is tied to how much mRNA is expressed from the active (PAV) form of the receptor, a concept called allele-specific expression (12). For example, this is the case when analyzing caffeine consumption, which strongly correlates with active mRNA expression (12). The investigators therefore hypothesize that the abundance of active TAS2R38 mRNA in heterozygous individuals also predicts the biologically significant change in magnitude of defensive responses in the presence of AHLs (13-15). The proposed study will determine whether this is in fact the case, and whether those people who have high mRNA abundance in taste tissue (fungiform papillae) also have correspondingly high abundance in nasal epithelium, or whether regulation is tissue-dependent. This will allow us to determine whether taste tests could provide a reliable representation of receptor function in other tissues and cell types. Should mRNA abundance prove to be a key factor, the investigators will determine whether high expressers sustain this expression over time.
Of note, a study performed by Dr. Reed and collaborators found that the population in Philadelphia contained 18% of individuals in the homozygous nontaster (AVI) group, 17% in the homozygous taster (PAV) group and 37% in the common heterozygous group (AVI/PAV) (16). The remaining 28% were distributed among ten other less common genotypes, which will not be analyzed in this study. Thus, as the majority of the population is heterozygous, a thorough understanding of their ability to fight infection is clinically important.
Clinical Significance. As one of the most common chronic conditions in the United States, chronic rhinosinusitis invokes a direct treatment cost of $3.5-5 billion annually. Its incidence is 146 per 1,000 and increasing (17). Our prior studies have shown that individuals with two copies of the active form of T2R38 have nasal epithelium that defends very effectively against certain bacteria, such as Pseudomonas aeruginosa, and are less likely to develop severe chronic rhinosinusitis requiring surgery, while those with two inactive forms cannot defend themselves as effectively, and are more likely to develop severe chronic rhinosinusitis requiring surgical intervention. Because the treatment of chronic rhinosinusitis involves multiple rounds of antibiotics and often surgical management through functional endoscopic sinus surgery (FESS), this research has significant implications for antibiotic stewardship, surgical morbidity and mortality, and health care expenditures.
Tarehe
Imethibitishwa Mwisho: | 12/31/2017 |
Iliyowasilishwa Kwanza: | 05/04/2016 |
Uandikishaji uliokadiriwa Uliwasilishwa: | 05/08/2016 |
Iliyotumwa Kwanza: | 05/09/2016 |
Sasisho la Mwisho Liliwasilishwa: | 09/16/2018 |
Sasisho la Mwisho Lilichapishwa: | 09/17/2018 |
Tarehe halisi ya kuanza kwa masomo: | 12/31/2015 |
Tarehe ya Kukamilisha Msingi iliyokadiriwa: | 07/31/2017 |
Tarehe ya Kukamilisha Utafiti: | 07/31/2018 |
Hali au ugonjwa
Uingiliaji / matibabu
Other: AVI/PAV.
Awamu
Vikundi vya Arm
Mkono | Uingiliaji / matibabu |
---|---|
PAV/PAV Tasters Individuals homozygous for the taster allele of the TAS2R38 gene, PAV/PAV. | |
AVI/PAV. Individuals heterozygous for the taster allele of the TAS2R38 gene, AVI/PAV. | Other: AVI/PAV. |
AVI/AVI Individuals homozygous for the non-taster allele of the TAS2R38 gene, AVI/AVI. |
Vigezo vya Kustahiki
Zama zinazostahiki Kujifunza | 21 Years Kwa 21 Years |
Jinsia Inastahiki Kujifunza | All |
Njia ya sampuli | Non-Probability Sample |
Hupokea Wajitolea wa Afya | Ndio |
Vigezo | Inclusion Criteria: - Key inclusion criteria include age 21-50 years - English speaking, and plans to undergo a sinonasal procedure for reconstructive purposes or other reasons. Exclusion Criteria: - Key exclusion criteria include a history of chronic rhinosinusitis - Plans to undergo a procedure for reasons other than reconstruction - Oral disease - Pregnancy, or any condition that would prevent psychophysical testing. - Subjects showing signs of oral disease, including tongue lesions or xerostomia, would be excluded from tongue sampling, and therefore excluded from the study. - Subjects will not be excluded because of economic status, gender, race or ethnicity. |
Matokeo
Hatua za Matokeo ya Msingi
1. TAS2R38 genotype [Up to 1 month after enrollment.]
2. TAS2R38 mRNA expression levels measured by RT-qPCR [Approximately 6 weeks after subject enrollment]
3. Ciliary beat frequency [Approximately 6 weeks after subject enrollment]
4. Production of nitric oxide by a participant's nasal epithelium culture measured in fold change of 4,5-diaminofluorescence diacetate [Approximately 6 weeks after subject enrollment]
Hatua za Matokeo ya Sekondari
1. Bitter taste perception as measured by a visual analog scale [Approximately 6 weeks after subject enrollment]
2. Caffeine intake measured by number caffeinated beverages consumed per week (normalized to 1 cup = 180 mg caffeine) [Approximately 6 weeks after subject enrollment]
3. Taste papillae density [Approximately 6 weeks after subject enrollment]