Pathways, mechanisms, and treatments of vocal communication deficits in a Parkinson rat model

帕金森大鼠模型声音沟通缺陷的途径、机制和治疗

• 批准号: 10188665
• 负责人: Cynthia A Kelm-Nelson
• 金额: $ 36.54万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10188665
• 关键词: Acoustics; Address; Affect; Age-Months; Animal Model; Animals; Behavior; Biochemistry; Biological; Brain Pathology; Brain Stem; Caring; Catalogs; Cell Culture Techniques; Clinical; Clinical Trials; Communication; Communication impairment; Data; Data Set; Disease; Disease Progression; Dopamine; Drug Kinetics; Drug Screening; Drug usage; Dysarthria; Dysphonia; Exhibits; FDA approved; Female; Functional disorder; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Human Genetics; Idiopathic Parkinson Disease; Image; In Vitro; Individual; Knock-out; Knowledge; Laryngeal muscle structure; Larynx; Measures; Methodology; Modeling; Molecular; Molecular Target; Motor Neurons; Motor Pathways; Nerve Degeneration; Nervous system structure; Neural Pathways; Neuraxis; Neurons; Outcome; PARK6 gene; PINK1 gene; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Population; Prevalence; Production; Quality of life; Rattus; Refractory; Research; Rodent Model; Science; Series; Social Interaction; Structure; System; Techniques; Therapeutic; Therapeutic Effect; Time; Tracer; Transcript; Voice; Work; base; brain tissue; clinically relevant; density; differential expression; disease diagnosis; drug candidate; drug repurposing; drug standard; early onset; experience; experimental study; functional outcomes; genetic variant; human subject; improved; in vivo; innovation; male; novel; novel therapeutics; patient population; prevent; public health relevance; response; sex; single-cell RNA sequencing; small molecule therapeutics; targeted treatment; theories; three-dimensional modeling; transcriptome sequencing; vocal cord; vocalization

PROJECT SUMMARY/ABSTRACT Greater than 90% of individuals with Parkinson disease (PD) experience significant vocal communication deficits that appear early in the manifestation of the disease, negatively impact quality of life, and are refractory to current therapeutic approaches. PD pathology occurs in both the central and peripheral nervous systems and differs according to sex, but how this affects vocal communication is unknown and presents a critical gap in knowledge, limiting current patient treatments. This research will elucidate how vocal dysfunction manifests at a biological and functional level. The long-term goal and primary objective of this work is to understand, prevent, and/or reverse vocal communication deficits in individuals with PD. To accomplish this, a validated rat model of PD, Pink1-/-, will be used. Male and female Pink1-/- rats show early, progressive vocal deficits with brainstem and laryngeal pathology that recapitulate the communication deficits observed in human PD. Based on preliminary data, this research will address the hypothesis that the neuroanatomical biochemistry of vocalization pathways in Pink1-/- rats is significantly different compared to wildtype control rats (Specific Aim 1). The rationale for this study is the need for basic, mechanistic information on sex-specific vocal pathways and respective connections that will be key targets to improve and/or modulate vocal behavior over time. By applying retrograde tracers into the vocal fold, the peripheral (larynx) to central (brainstem) connections will be assessed in Pink1-/- and control rats. Using 3D modeling, differences in the distribution and density of neurons within central nervous system vocalization pathways will be quantified. Because current treatments for PD voice deficits are insufficient, the second goal of this proposal is to address the hypothesis that currently approved therapeutics will be identified and validated for the treatment and modulation of PD vocal communication deficits (Specific Aim 2). The rationale for this work is the need for drugs that effectively modulate vocal production for future human PD clinical trials. Using gene targets from Pink1-/- larynx and brainstem datasets, a list of biologically relevant drugs will be generated using drug-repurposing catalogs. The application of selected drugs to in vitro Pink1-/- larynx as well as brainstem cell cultures will generate significant alterations in the gene transcript as quantified with single cell RNA-sequencing. To confirm efficacy, these therapeutics will be administered to Pink1-/- rats to measure in vivo vocalization improvements. The simultaneous administration of new drugs to both biological (cellular) and functional (animal) platforms provides distinct yet integrated information that is unable to be obtained from the human patient population. This approach is innovative because it incorporates new techniques and theory from molecular, physiological, and communication sciences and will provide in-depth knowledge of sex-specific PD vocalization deficits. This proposal is significant because it targets a voice research platform that addresses a clinically relevant, undertreated question and will directly impact the treatment of PD voice dysfunction.

项目概要/摘要 超过 90% 的帕金森病 (PD) 患者经历过明显的声音交流 在疾病表现早期出现的缺陷，对生活质量产生负面影响，并且是难治性的 目前的治疗方法。 PD 病理发生在中枢和周围神经系统中 并且因性别而异，但这如何影响声音交流尚不清楚，并且存在严重差距 知识，限制了当前患者的治疗。这项研究将阐明发声功能障碍如何表现 在生物学和功能水平上。这项工作的长期目标和主要目标是了解， 预防和/或逆转帕金森病患者的声音沟通缺陷。为了实现这一目标，经过验证的老鼠 将使用 PD 型号 Pink1-/-。雄性和雌性 Pink1-/- 大鼠表现出早期、进行性的声音缺陷 脑干和喉部病理学概括了在人类 PD 中观察到的沟通缺陷。基于 根据初步数据，本研究将提出以下假设： Pink1-/- 大鼠的发声途径与野生型对照大鼠显着不同 （具体目标1）。这项研究的基本原理是需要有关性别特异性的基本、机制信息 声音通路和各自的连接将成为改善和/或调节声音行为的关键目标 随着时间的推移。通过将逆行示踪剂应用到声带、外围（喉）到中央（脑干） 将在 Pink1-/- 和对照大鼠中评估连接。使用 3D 建模，分布和 中枢神经系统发声通路内神经元的密度将被量化。因为目前 对于 PD 声音缺陷的治疗还不够，该提案的第二个目标是解决这一假设 目前批准的治疗方法将被识别和验证用于治疗和调节 PD 声音沟通缺陷的研究（具体目标 2）。这项工作的基本原理是需要药物 有效调节未来人类帕金森病临床试验的发声。使用 Pink1-/- 的基因靶标 喉和脑干数据集，将使用药物再利用生成生物学相关药物的列表 目录。所选药物在体外 Pink1-/- 喉以及脑干细胞培养中的应用将 通过单细胞 RNA 测序定量，基因转录物产生显着改变。确认 功效，这些疗法将被给予 Pink1-/- 大鼠以测量体内发声的改善。 新药同时给药于生物（细胞）和功能（动物）平台 提供了无法从人类患者群体中获得的独特但综合的信息。 这种方法是创新的，因为它结合了分子、生理、 和传播科学，并将提供有关性别特异性 PD 发声缺陷的深入知识。这 该提案意义重大，因为它针对的是一个解决临床相关问题的语音研究平台， 治疗不足的问题将直接影响PD语音功能障碍的治疗。