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

声音障碍治疗的安全性和有效性的临床前测试

• 批准号: 9197550
• 负责人: Bernard Rousseau
• 金额: $ 64.07万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197550
• 关键词: Acute; Address; Adult; Adverse effects; Allergic; Allergic rhinitis; Anti-Inflammatory Agents; Anti-inflammatory; Area; Asthma; Caring; Cell physiology; Cell surface; Censuses; Chronic Obstructive Airway Disease; Clinical; Development; Diabetes Mellitus; Direct Costs; Disease; Drug usage; Dysphonia; Epithelial; Evaluation; Family; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Proteins; Genetic Transcription; Glucocorticoids; Goals; Human; Impairment; In Vitro; Income; Inflammatory; Intercellular Junctions; Larynx; Lateral; Lead; Lesion; Maintenance; Measurement; Measures; Messenger RNA; Molecular; Morphology; National Institute on Deafness and Other Communication Disorders; Organ; Otolaryngology; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiology; Population; Positioning Attribute; Pre-Clinical Model; Prevalence; Protein Biosynthesis; Public Health; Regulation; Research; Resistance; Role; Safety; Societies; Strategic Planning; Structure; Surface; System; Testing; Therapeutic; Tissues; Transcript; Translations; Treatment Cost; Treatment Efficacy; United States; Voice; Voice Disorders; Wages; beta catenin; density; disability; disability payment; efficacy research; experience; improved; in vivo; insight; novel strategies; occludin; pre-clinical; preclinical study; programs; protein expression; protein structure function; research clinical testing; steroid hormone; vocal cord

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.

项目概要 美国成年人中嗓音障碍的终生患病率为 30%（点患病率） 税率为 6.6% 至 7.5%。这些疾病使人衰弱，并可能导致严重的社会情感问题 后果、收入损失和长期残疾。点流行率和人口普查估计表明 每年有近 20-2300 万成年人可能出现发声困难，并导致治疗费用和工资损失 接近130亿美元。这些年度直接成本与慢性病相关的成本相当。 阻塞性肺病、哮喘、糖尿病和过敏性鼻炎。在耳鼻喉科评估中 发声困难，近 43% 的短期残疾索赔与语音损伤相关。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 作为满足这一需求的重要第一步，我们的研究计划已在以下领域开展了系统性工作： 声音障碍领域的发现和临床前测试。迄今为止，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以及可以 支持临床前模型中基因/蛋白质、结构和功能的研究。在这个五年计划中，我们 将我们的努力集中在急性语音创伤治疗的安全性和有效性上。我们专注于一类 尽管对机制和适应症的了解有限，但类固醇激素在人类中广泛使用 用于使用、安全性和功效证明。除了抗炎作用之外，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，糖皮质激素具有 发展成为许多炎症性疾病和涉及上皮受损的疾病的一线治疗 屏障功能。不幸的是，尽管糖皮质激素在临床上广泛使用，但其对 声带上皮屏障仍然未知。需要进行嗓音障碍治疗效果研究 被认为是 NIDCD 战略计划的高度优先领域。 I/II/III期开发 人体临床试验很大程度上依赖于临床前研究来提供有关 治疗安全性和有效性的机制。联邦法规要求证明安全性 和在批准大规模人体试验之前的功效。因此，临床前测试不仅是必要的 改善护理，同时也减轻声音障碍给患者和社会带来的负担。为了解决这一需求， 我们的研究计划处于有利位置，可以针对嗓音障碍治疗的功效开展系统性工作。在当前的提案中，我们将使用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、所需活性和药物安全性 糖皮质激素。