Pre-Clinical Testing of the Safety and Efficacy of Treatments for Voice Disorders

项目摘要 美国成年人群中发声障碍的终生患病率为30%，点患病率为30% 税率在6.6%至7.5%之间。这些障碍会使人虚弱，并可能导致严重的社会情绪 后果、收入损失和长期残疾。点位流行率和人口普查估计表明 每年近2,000-2,300万成年人可能会经历发音困难，并伴随着治疗费用和工资损失 接近130亿美元。这些年的直接成本与慢性疾病相关的成本相当 阻塞性肺病、哮喘、糖尿病和过敏性鼻炎。在耳鼻咽喉科评估中 发音困难，近43%的短期残疾索赔与声音创伤损伤有关。因此， 改善嗓音障碍患者的护理仍然是一项重要的公共卫生需求。作为必要的 为了满足这一需求，我们的研究计划已经在以下方面建立了系统的努力 在发声障碍领域的发现和临床前测试。到目前为止，我们的努力提供了关键的 对声音创伤的细胞和分子病理生理学的新见解和新的方法 支持临床前模型中的基因/蛋白质、结构和功能研究。在这个五年计划中，我们 将我们的精力集中在急性声音创伤治疗的安全性和有效性上。我们关注的是一类 类固醇激素在人类中广泛使用，尽管对机制和适应症的了解有限 用于使用、安全和药效演示。除了抗炎行动，新出现的证据 支持糖皮质激素在维持上皮屏障中的作用。因此，糖皮质激素对 发展成为许多炎症性疾病和涉及受损上皮的疾病的一线治疗方法 屏障功能。不幸的是，尽管临床广泛使用，糖皮质激素对 声带上皮屏障仍不清楚。对发声障碍的治疗效果研究的需要 被确认为NIDCD战略计划的高度优先领域。I/II/III阶段的发展 在人体上的临床试验强烈依赖于临床前研究，以提供关于 治疗安全性和有效性的潜在机制。联邦法规要求展示安全性 以及在大规模人体试验获得批准之前的疗效。因此，临床前测试不仅是必要的 改善护理，也是为了减轻患者和社会的嗓音障碍负担。为了满足这一需求， 我们的研究计划处于有利地位，可以对语音障碍治疗的有效性展开系统的努力。在目前的方案中，我们将在体外和体内测试糖皮质激素的药效学。 体内临床前模型，以确定作用机制、预期活性和药物安全性概况 糖皮质激素。

Project Summary The lifetime prevalence of voice disorders in the adult United States population is 30% with point prevalence rates of 6.6% to 7.5%. These disorders are debilitating and can lead to significant socioemotional consequences, loss of income, and long-term disability. Point prevalence and census estimates suggest that nearly 20-23 million adults may experience dysphonia annually, with the cost of treatment and lost wages approaching $13 billion dollars. These annual direct costs are comparable to those associated with chronic obstructive pulmonary disease, asthma, diabetes, and allergic rhinitis. Among otolaryngology evaluations for dysphonia, nearly 43% of short-term disability claims are associated with phonotraumatic lesions. Thus, improving the care of patients with voice disorders remains a significant public health need. As a necessary and essential first step to address this need, our research program has established a systematic effort in discovery and pre-clinical testing in the area of voice disorders. Our efforts to date have provided critical new insights into the cellular and molecular pathophysiology of phonotrauma and novel approaches that can support studies of gene/protein, structure, and function in pre-clinical models. In this five-year proposal, we concentrate our efforts on the safety and efficacy of treatments for acute phonotrauma. We focus on a class of steroid hormones extensively used in humans, despite a limited understanding of mechanisms and indications for use, safety, and demonstration of efficacy. Beyond the anti-inflammatory actions, emerging evidence supports a role for glucocorticoids in the maintenance of the epithelial barrier. As a result, glucocorticoids have evolved as a first line therapy for many inflammatory diseases and disorders involving impaired epithelial barrier function. Unfortunately, despite widespread clinical use, the specific effects of glucocorticoids on the vocal fold epithelial barrier remain unknown. The need for treatment efficacy research in voice disorders has been acknowledged as a high priority area in the NIDCD strategic plan. The development of phase I/II/III clinical testing in humans strongly depends on pre-clinical studies to provide information regarding mechanisms underlying therapeutic safety and efficacy. Federal regulations require demonstration of safety and efficacy prior to the approval of large-scale human trials. Pre-clinical testing is thus necessary not only to improve care, but also to reduce the burden of voice impairment on patients and society. To address this need, our research program is well-positioned to launch a systematic effort on the efficacy of treatments for voicedisorders. In the current proposal, we will test the pharmacodynamics of glucocorticoids using in vitro and in vivo preclinical models in order to determine the mechanism of action, desired activity, and drug safety profile of glucocorticoids.