Chronic Rhinosinusitis and genetics of bitter taste receptors

描述（由申请人提供）：我们最近证明苦味受体T2R38在上呼吸道中表达，并被酰基高丝氨酸内酯（AHLs）激活：由铜绿假单胞菌和其它革兰氏阴性菌分泌的群体感应分子。 此外，我们发现T2R38通过一氧化氮的产生来调节人类上呼吸道的先天防御，这刺激了粘膜纤毛的清除并具有直接的抗菌作用。 此外，与对PTC分子的味觉敏感性相关的TAS2R38基因的常见多态性与上呼吸道细胞响应AHLs清除和杀死细菌的能力的显著差异有关。 基于这些结果，我们的中心假设是，苦味受体T2R38在上呼吸道上皮细胞中表达，构成了一个前哨防御网络，用于检测和清除微生物，T2R38的遗传变异有助于气道防御能力的个体差异。 为了验证这个假设，我们将：（1）确定TAS2R38基因型、PTC味觉敏感性和等位基因特异性表达是否与慢性鼻窦炎（CRS）的症状严重程度、疾病负担和干预结果相关，以及未被AHL激活的TAS2R38多态性是否在CRS患者组群中过度表达，和（2）鉴定激活TAS2R38的常见遗传变体的其它微生物产物。 这些目标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性如何导致上呼吸道疾病。此外，我们将确定苦味敏感性是否可以作为慢性鼻窦炎患者疾病严重程度的指标，以及该途径的药理学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.