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

项目概要/摘要 超过90%的帕金森病（PD）患者经历了重要的语音交流 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病理发生在中枢和外周神经系统中 根据性别而不同，但这如何影响声音交流是未知的，并提出了一个关键的差距， 限制了目前的患者治疗。这项研究将阐明如何发声功能障碍表现 在生物和功能层面上。这项工作的长期目标和主要目标是了解， 预防和/或逆转PD患者的语音沟通缺陷。为了实现这一目标， 将使用PD模型Pink1-/-。雄性和雌性Pink1-/-大鼠表现出早期的、进行性的发声缺陷， 脑干和喉病理学，重现了在人类PD中观察到的沟通缺陷。基于 根据初步数据，这项研究将解决这一假设，即神经解剖生物化学的 Pink 1-/-大鼠的发声途径与野生型对照大鼠相比有显著差异 （具体目标1）。这项研究的基本原理是需要关于性别特异性的基本的、机械的信息。 发声通路和相应的连接，将是改善和/或调节发声行为的关键目标 随着时间通过应用逆行示踪剂进入声带，外周（喉）到中央（脑干） 将在Pink 1-/-和对照大鼠中评估连接。使用3D建模， 将量化中枢神经系统发声通路内的神经元密度。因为当前 PD语音缺陷的治疗是不够的，这项建议的第二个目标是解决假设 目前批准的治疗药物将被鉴定和验证用于治疗和调节 PD语音沟通缺陷（具体目标2）。这项工作的基本原理是需要药物， 有效地调节发声，用于未来的人类PD临床试验。使用来自Pink1-/-的基因靶点 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。将选定的药物应用于体外Pink 1-/-喉细胞以及脑干细胞培养将 在基因转录物中产生显著改变，如用单细胞RNA测序所定量。确认 为了提高疗效，将这些治疗剂施用于Pink 1-/-大鼠以测量体内发声改善。 同时向生物（细胞）和功能（动物）平台施用新药 提供了无法从人类患者群体中获得的独特但完整的信息。 这种方法是创新的，因为它结合了分子，生理， 和通信科学，并将提供深入了解性别特异性PD发声缺陷。这 该提案意义重大，因为它针对的是一个语音研究平台， 治疗不足的问题，将直接影响PD语音功能障碍的治疗。

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.