Novel mechanisms and therapeutic approaches for nasal obstruction and olfactory losses

项目摘要 鼻窦疾病是美国最常见的医疗疾病之一，影响 据估计，13%的成年人，即约3000万人，负责58亿美元的健康 每年的保健支出(2009年全国健康访谈调查，CDC)。鼻塞 和嗅觉丧失是该病的两个主要症状；然而，该领域目前缺乏 对导致这些症状的机制有一个清晰、客观的认识，这阻碍了 有效的治疗。例如，患者对鼻塞的抱怨相关性较差或 与实际物理障碍的客观测量不一致。嗅觉丧失是 人们普遍认为，部分原因是气流阻塞，阻止了足够的环境气味 到达嗅觉区域；然而，还没有工具能够评估和定位这样的 传导原因。如果没有经过验证的临床工具，目前对这些症状的治疗依赖于 主要是根据患者的主观反馈和医生的个人培训和经验， 这可能会导致不一致和不令人满意的结果。 通过一系列的初步研究，我们证明了鼻炎的症状 阻塞可能不是由阻塞本身引起的，而是由于在 呼吸，通过三叉神经冷敏感(TRPM8)通路，这种感觉可能 因三叉神经功能受损而恶化。然而，哪些三叉神经感觉区和 目前尚不清楚哪些鼻部气流异常对气流感觉的影响最为严重。 为了建立更直接的联系，在本提案的目标1中，我们将检查关键的三叉神经 可更好地预测气流知觉的感觉区域和临界鼻流扭曲 和梗阻症状。TRPM8是冷传入通路的主要组成部分，即 也是化学激活的，这提供了一种独特的双重调查工具来扩大我们的 认识鼻窦疾病的化学感觉功能开辟治疗新途径 方向。因此，在目标2中，我们将研究一种正在申请专利的新型鼻塞的疗效。 通过调节鼻腔气流和三叉神经感觉反馈改善患者的症状 根据我们已经学到并将继续学到的东西，改善未来的治疗结果 关于气流的三叉神经知觉机制。 我们还在一系列已发表的研究中表明，存在复杂的关系 鼻塞和嗅觉功能之间的关系。基于这些发现，在目标3中，我们建议 探讨如何潜在地改善潜在传导障碍患者的嗅觉功能 嗅觉丧失，通过增加鼻气味/空气流向嗅觉区域(另一项悬而未决的美国 专利)，类似于助听器或眼镜，可以放大周围的感官刺激。 这项研究的结果可能会潜在地验证几种新的临床工具 更好地识别对患者梗阻症状影响最大的因素并缓解症状 通过调节鼻腔气流模式。最终目标是帮助患者和临床医生 规划有效、消息灵通、个性化的治疗策略，可能会节省数百万美元 在提高患者满意度的同时，每年减少医疗保健费用。

Project Summary Nasal sinus disease is one of the most common medical conditions in the US, affecting an estimated 13% of adults, or some 30 million people, and responsible for $5.8 billion in health care expenditures annually (National Health Interview Survey 2009, CDC). Nasal obstruction and smell loss are two of the major symptoms of the disease; however, the field currently lacks a clear, objective understanding to the mechanisms causing these symptoms, which thwarts effective treatment. For example, patients’ complaints of nasal obstruction correlate poorly or inconsistently with objective measurements of actual physical obstruction. Olfactory loss is widely believed to be induced in part by airflow blockage that prevents sufficient ambient odor from reaching the olfactory region; however, no tool has been able to evaluate and target such conductive causes. Without validated clinically tools, current treatment of these symptoms relies primarily on the patient’s subjective feedback and the doctor’s personal training and experience, which can lead to inconsistent and unsatisfactory outcomes. Through a series of preliminary studies, we demonstrated that the symptom of nasal obstruction may be caused not by obstruction per se but by poor sensing of airflow during breathing, through the trigeminal cool-sensitive (TRPM8) pathway, and that such sensing may be worsened by impaired trigeminal function. However, which trigeminal sensory regions and what nasal airflow anomalies are most critical to disrupt the sensing of airflow are still unknown. To establish a more direct link, in Aim 1 of this proposal, we will examine the critical trigeminal sensory regions and critical nasal airflow distortions that may better predict airflow perception and obstruction symptoms. TRPM8 is a major component of the cool afferent pathway that is also activated chemically, which offers a unique dual investigatory tool to broaden our understanding of chemosensory function in nasal sinus disease and open up new therapeutic directions. So in Aim 2, we will investigate the efficacy of a novel patent-pending “nasal aid” to improve patients’ symptoms by modulating nasal airflow and trigeminal sensory feedback and to improve future treatment outcomes based on what we have learned and will continue to learn about the airflow trigeminal perception mechanisms. We have also shown in a series of published studies that complicated relationships exist between nasal obstruction and olfactory function. Based on these findings, in Aim 3 we propose to explore how to potentially improve olfactory function in patients with likely conductive olfactory loss, by enhancing nasal odor/air flow to the olfactory region (another pending US patent), analogous to hearing aids or eye glasses that amplify peripheral sensory stimuli. The outcomes from this research may potentially validate several novel clinical tools to better identify factors that most affect patients’ obstructive symptoms and to relieve symptoms by modulating nasal airflow patterns. The ultimate goal is to assist patients and clinicians in planning effective, well-informed, personalized treatment strategies, potentially saving millions of health care dollars annually while improving patient satisfaction.