Chronic Rhinosinusitis and genetics of bitter taste receptors

描述(申请人提供)：我们最近证明苦味受体T2R38在上呼吸道表达，并被酰基高丝氨酸内酯(AHLS)激活，AHLS是铜绿假单胞菌和其他革兰氏阴性细菌分泌的群体感应分子。此外，我们发现T2R38通过产生一氧化氮来调节人类上呼吸道的先天防御，从而刺激粘液纤毛清除，并具有直接的抗菌作用。此外，TAS2R38基因的常见多态与味道对PTC分子的敏感性有关，与上呼吸道细胞清除和杀灭细菌对AHLS的反应能力的显著差异有关。基于这些结果，我们的中心假设是，表达在上呼吸道上皮细胞中的苦味受体T2R38构成了检测和清除微生物的哨兵防御网络，T2R38的基因变异导致了呼吸道防御能力的个体差异。为了验证这一假说，我们将：(1)确定TAS2R38基因型、PTC口味敏感性和等位基因特异性表达是否与慢性鼻-鼻窦炎(CRS)的症状严重程度、疾病负担和干预结果相关，以及(2)确定激活TAS2R38常见遗传变体的其他微球产品是否在CRS患者队列中过度表达。这些目的的目的是确定苦味受体T2R38在上呼吸道防御中的作用，以及该受体的常见多态如何促进上呼吸道疾病。此外，我们将确定苦味敏感性是否可以作为慢性鼻-鼻窦炎患者病情严重程度的指标，以及对这一途径的药物操作是否具有治疗潜力。

DESCRIPTION (provided by applicant): We have recently demonstrated that the bitter taste receptor T2R38 is expressed in the upper airway and is activated by acyl-homoserine lactones (AHLs): quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Furthermore, we found that T2R38 regulates human upper airway innate defenses through nitric oxide production, which stimulates mucociliary clearance and has direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene, correlating with taste sensitivity to the molecule PTC, are linked to significant differences in the ability of uppe respiratory cells to clear and kill bacteria in response to AHLs. Based on these results, our central hypothesis is that the bitter taste receptor T2R38 expressed in the upper respiratory epithelium constitutes a sentinel defense network for the detection and clearance of microbes and that genetic variation in T2R38 contributes to individual differences in airway defensive capabilities. To test this hypothesis, we will: (1) determine whether TAS2R38 genotype, PTC taste sensitivity, and allele-specific expression correlate with symptom severity, disease burden, and interventional outcomes of chronic rhinosinusitis (CRS), and whether TAS2R38 polymorphisims not activated by AHLs are overrepresented in a cohort of CRS patient, and (2) identify other micorbial products that activate the common genetic variants of TAS2R38. The goal of these aims is to determine the role the bitter taste receptor T2R38 plays in upper airway defense and how common polymorphisms of this receptor contribute to upper airway disease. Furthermore, we will determine whether bitter taste sensitivity can be used as an indicator for disease severity in patients with chronic rhinosinusitis, and whether pharmacologic manipulation of this pathway has therapeutic potential.