Chronic Rhinosinusitis and genetics of bitter taste receptors

慢性鼻窦炎与苦味受体遗传学

基本信息

批准号：
8850843
负责人：
Noam A Cohen
金额：
$ 43.35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850843
关键词：
Age Agonist Alleles Anti-Bacterial Agents Bacteria Brain Breathing Cells Chemicals Clinical Complex Data Detection Disease Environmental Exposure Epithelial Equilibrium Etiology Exposure to Failure Frequencies Functional disorder Gender Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genotype Goals Gram-Negative Bacteria Health Human Individual Individual Differences Infection Ligands Link Measures Medical Microbe Mucociliary Clearance Mucosal Immunity Natural Immunity Nitric Oxide Nose Operative Surgical Procedures Oral cavity Outcome Pathway interactions Patients Play Predisposition Prevalence Process Production Pseudomonas aeruginosa Publishing Race Respiratory Tract Infections Role Sentinel Severities Severity of illness Signal Transduction Sinus Structure of respiratory epithelium Symptoms System Taste Buds Taste Perception Testing Therapeutic Tissues Variant antimicrobial bactericide base burden of illness chronic rhinosinusitis cohort defense response enteric pathogen genetic variant high throughput screening homoserine lactone killings microbial pathogen prognostic quorum sensing receptor respiratory response screening success

项目摘要

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.

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（AHL）激活：酰基高丝氨酸内酯（AHL）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通过一氧化氮的产生调节人类上呼吸道先天防御，一氧化氮刺激粘液纤毛清除并具有直接抗菌作用。此外，TAS2R38 基因的常见多态性与对 PTC 分子的味觉敏感性相关，与上呼吸道细胞响应 AHL 清除和杀死细菌的能力的显着差异有关。基于这些结果，我们的中心假设是，上呼吸道上皮表达的苦味受体T2R38构成了检测和清除微生物的哨兵防御网络，并且T2R38的遗传变异导致气道防御能力的个体差异。为了检验这一假设，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 TAS2R38 多态性是否未被激活AHL 在 CRS 患者队列中的比例过高，并且 (2) 识别出其他激活 AHL 常见遗传变异的微生物产物TAS2R38。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用作慢性鼻窦炎患者疾病严重程度的指标，以及该途径的药理操作是否具有治疗潜力。