Allele-specific Expression of a Bitter Taste Receptor

NCT02766959 | Completed

• 1 other identifier: 823078
• Study Type: observational
• Target: 57
• Locations: 1 country
• Sites: 3

Brief Summary

This single-site, within-subject experimental basic research study is designed to analyze the hypothesis that allele-specific expression of the bitter taste receptor T2R38 in taste tissue of individuals heterozygous for the taste receptor gene TAS2R38 correlates with that in nasal epithelium, and is responsible for differences in acyl-homoserine lactone-induced respiratory defenses. Subjects will include 100 predominantly European adults without chronic rhinosinusitis who will be undergoing a sinonasal procedure for reconstructive purposes. All subjects will provide saliva samples for genotyping, from which 25 subjects heterozygous for TAS2R38 (AVI/PAV) will be identified. These individuals will be asked to complete a beverage frequency questionnaire and taste test prior to the procedure that will evaluate for a number of compounds, among them bitter ligands specific to T2R38. Their tongue will also be photographed to evaluate the anatomy of their fungiform papillae, the mushroom-like structures on the tongue which contain taste buds. Subjects will subsequently provide nasal epithelium and taste tissue, which will be processed to 1) evaluate for allele-specific expression of TAS2R38 mRNA in both the taste and nasal tissue, with the nasal tissue concurrently being cultured in an air-liquid interface system to 2) assess the AHL-induced respiratory defenses of ciliary beat frequency (CBF) and nitric oxide (NO) production. Should subjects require a subsequent sinonasal procedure for clinically-determined reasons, taste and nasal tissue will again be obtained and analyzed for TAS2R38 mRNA, allowing for 3) longitudinal evaluation of mRNA expression level.

Conditions

Rhinosinusitis

Keywords

chronic rhinosinusitis; airway physiology; taste receptors; tas2r; epithelial biology; upper respiratory disease

Outcome Measures

Primary Outcomes (4)

• TAS2R38 genotype

  A participant's genotype will be identified on enrollment in the study, the results of which could take up to 1 month to be performed.

  Up to 1 month after enrollment.

• TAS2R38 mRNA expression levels measured by RT-qPCR

  Measured approximately 6 weeks after enrollment, based on the date of the participant's procedure.

  Approximately 6 weeks after subject enrollment

• Ciliary beat frequency

  Measured approximately 6 weeks after enrollment, based on the date of the participant's procedure.

  Approximately 6 weeks after subject enrollment

• Production of nitric oxide by a participant's nasal epithelium culture measured in fold change of 4,5-diaminofluorescence diacetate

  The production of nitric oxide (NO) by a patient's nasal epithelium culture will be measured approximately 6 weeks after enrollment, based on the date of his or her procedure. This will be measured by quantifying the fold change in fluorescence by using the NO-sensitive marker 4,5-diaminofluorescence diacetate (DAF-2).

  Approximately 6 weeks after subject enrollment

Secondary Outcomes (3)

• Bitter taste perception as measured by a visual analog scale

  Approximately 6 weeks after subject enrollment

• Caffeine intake measured by number caffeinated beverages consumed per week (normalized to 1 cup = 180 mg caffeine)

  Approximately 6 weeks after subject enrollment

• Taste papillae density

  Approximately 6 weeks after subject enrollment

Study Arms (3)

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: Observational study

AVI/AVI

Individuals homozygous for the non-taster allele of the TAS2R38 gene, AVI/AVI.

Interventions

Observational study OTHER

AVI/PAV.

Eligibility Criteria

• Age: 21 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

One hundred subjects will be tested for TAS2R38 genotype. Our typical subject population is approximately 82% of European descent and 35% female. All subjects will be recruited from those seen in the department of otorhinolaryngology's rhinology division and planning to undergo a sinonasal procedure for reconstructive purposes. The initial interview will occur in the clinic setting. From these 100 subjects, 25 who are heterozygous for TAS2R38 will be asked to perform a taste test, complete a beverage frequency questionnaire, have their tongue photographed, and provide nasal epithelium and taste tissue during their procedure. Key exclusion criteria include a history of chronic rhinosinusitis, oral disease, and any condition that would prevent them from completing the psychophysical testing.

You may qualify if:

• English speaking, and plans to undergo a sinonasal procedure for reconstructive purposes or other reasons.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Monell Chemical Senses Center: lead
• University of Pennsylvania: collaborator
• Corporal Michael J. Crescenz VA Medical Center: collaborator

Study Sites (3)

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Monell Chemical Senses Center

Philadelphia, Pennsylvania, 19104, United States

Location

Philadelphia Veterans Affairs Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (19)

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  PMID: 11101467 BACKGROUND

• Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS. A novel family of mammalian taste receptors. Cell. 2000 Mar 17;100(6):693-702. doi: 10.1016/s0092-8674(00)80705-9.

  PMID: 10761934 BACKGROUND

• Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ. T2Rs function as bitter taste receptors. Cell. 2000 Mar 17;100(6):703-11. doi: 10.1016/s0092-8674(00)80706-0.

  PMID: 10761935 BACKGROUND

• Lee RJ, Xiong G, Kofonow JM, Chen B, Lysenko A, Jiang P, Abraham V, Doghramji L, Adappa ND, Palmer JN, Kennedy DW, Beauchamp GK, Doulias PT, Ischiropoulos H, Kreindler JL, Reed DR, Cohen NA. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J Clin Invest. 2012 Nov;122(11):4145-59. doi: 10.1172/JCI64240. Epub 2012 Oct 8.

  PMID: 23041624 BACKGROUND

• Lee RJ, Kofonow JM, Rosen PL, Siebert AP, Chen B, Doghramji L, Xiong G, Adappa ND, Palmer JN, Kennedy DW, Kreindler JL, Margolskee RF, Cohen NA. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J Clin Invest. 2014 Mar;124(3):1393-405. doi: 10.1172/JCI72094. Epub 2014 Feb 17.

  PMID: 24531552 BACKGROUND

• Tizzano M, Gulbransen BD, Vandenbeuch A, Clapp TR, Herman JP, Sibhatu HM, Churchill ME, Silver WL, Kinnamon SC, Finger TE. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3210-5. doi: 10.1073/pnas.0911934107. Epub 2010 Jan 26.

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• Mueller KL, Hoon MA, Erlenbach I, Chandrashekar J, Zuker CS, Ryba NJ. The receptors and coding logic for bitter taste. Nature. 2005 Mar 10;434(7030):225-9. doi: 10.1038/nature03352.

  PMID: 15759003 BACKGROUND

• Bufe B, Breslin PA, Kuhn C, Reed DR, Tharp CD, Slack JP, Kim UK, Drayna D, Meyerhof W. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception. Curr Biol. 2005 Feb 22;15(4):322-7. doi: 10.1016/j.cub.2005.01.047.

  PMID: 15723792 BACKGROUND

• Wooding S, Bufe B, Grassi C, Howard MT, Stone AC, Vazquez M, Dunn DM, Meyerhof W, Weiss RB, Bamshad MJ. Independent evolution of bitter-taste sensitivity in humans and chimpanzees. Nature. 2006 Apr 13;440(7086):930-4. doi: 10.1038/nature04655.

  PMID: 16612383 BACKGROUND

• Kim UK, Jorgenson E, Coon H, Leppert M, Risch N, Drayna D. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide. Science. 2003 Feb 21;299(5610):1221-5. doi: 10.1126/science.1080190.

  PMID: 12595690 BACKGROUND

• Mennella JA, Pepino MY, Duke FF, Reed DR. Psychophysical dissection of genotype effects on human bitter perception. Chem Senses. 2011 Jan;36(2):161-7. doi: 10.1093/chemse/bjq106. Epub 2010 Oct 27.

  PMID: 20980355 BACKGROUND

• Lipchock SV, Mennella JA, Spielman AI, Reed DR. Human bitter perception correlates with bitter receptor messenger RNA expression in taste cells. Am J Clin Nutr. 2013 Oct;98(4):1136-43. doi: 10.3945/ajcn.113.066688. Epub 2013 Sep 11.

  PMID: 24025627 BACKGROUND

• Bartoshuk LM, Duffy VB, Miller IJ. PTC/PROP tasting: anatomy, psychophysics, and sex effects. Physiol Behav. 1994 Dec;56(6):1165-71. doi: 10.1016/0031-9384(94)90361-1.

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• Delwiche JF, Buletic Z, Breslin PA. Relationship of papillae number to bitter intensity of quinine and PROP within and between individuals. Physiol Behav. 2001 Oct;74(3):329-37. doi: 10.1016/s0031-9384(01)00568-6.

  PMID: 11714496 BACKGROUND

• Melis M, Atzori E, Cabras S, Zonza A, Calo C, Muroni P, Nieddu M, Padiglia A, Sogos V, Tepper BJ, Tomassini Barbarossa I. The gustin (CA6) gene polymorphism, rs2274333 (A/G), as a mechanistic link between PROP tasting and fungiform taste papilla density and maintenance. PLoS One. 2013 Sep 9;8(9):e74151. doi: 10.1371/journal.pone.0074151. eCollection 2013.

  PMID: 24040192 BACKGROUND

• Mennella JA, Pepino MY, Duke FF, Reed DR. Age modifies the genotype-phenotype relationship for the bitter receptor TAS2R38. BMC Genet. 2010 Jul 1;11:60. doi: 10.1186/1471-2156-11-60.

  PMID: 20594349 BACKGROUND

• Pleis JR, Lucas JW. Summary health statistics for U.S. adults: National Health Interview Survey, 2007. Vital Health Stat 10. 2009 May;(240):1-159.

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• Suitor CJ, Gardner J, Willett WC. A comparison of food frequency and diet recall methods in studies of nutrient intake of low-income pregnant women. J Am Diet Assoc. 1989 Dec;89(12):1786-94.

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• Spielman AI, Pepino MY, Feldman R, Brand JG. Technique to collect fungiform (taste) papillae from human tongue. J Vis Exp. 2010 Sep 18;(42):2201. doi: 10.3791/2201.

  PMID: 20972388 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

In part one of the study, each subject will provide a saliva sample. DNA will be isolated, purified, and quantitated for alleles of TAS2R38, a bitter taste receptor gene. Based on the results of the genetic screen, 25 individuals with the heterozygous genotype will be invited to return for part two of the study. In part two of the study, subject will provide nasal epithelium and taste tissue in the form of fungiform papillae. One half of each set of tissue will be placed in saline on ice in preparation for cell culture and assessment of AHL-induced defensive responses, while the second half will be placed in RNA preservative for mRNA isolation.

MeSH Terms

Conditions

Rhinosinusitis; Respiration Disorders

Interventions

Observation

Condition Hierarchy (Ancestors)

Rhinitis; Respiratory Tract Infections; Infections; Sinusitis; Paranasal Sinus Diseases; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases

Intervention Hierarchy (Ancestors)

Methods; Investigative Techniques

Study Officials

• Danielle R. Reed, Ph.D.

  Monell Chemical Senses Center

  PRINCIPAL INVESTIGATOR

• Noam A. Cohen, M.D., Ph.D.

  Monell Chemical Senses Center, University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 5, 2016
• First Posted: May 10, 2016
• Study Start: January 1, 2016
• Primary Completion: August 1, 2017
• Study Completion: August 1, 2018
• Last Updated: September 18, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)