Influence of neuromuscular pathology on parkinsonian communication deficits

 描述（由申请人提供）：帕金森病（PD）患者经历毁灭性的沟通和吞咽缺陷，对生活质量产生负面影响。最近的研究表明，PD病理学是广泛的，不仅包括中枢神经系统区域，而且包括外周结构，如参与交流和吞咽的神经和肌肉。然而，尽管有这些最近的数据，很少有人知道外周病变如何有助于沟通和吞咽缺陷，以及在疾病过程中，这些缺陷出现。此外，目前尚不清楚临床上使用的行为治疗，如基于运动的声音和吞咽疗法，如何影响这些缺陷的表现。为了开发更有效的治疗方法，必须清楚地了解外周病变的进展以及这些病变影响交流和吞咽的方式。这些未知因素将在拟议的研究中通过研究一种渐进的新型PD遗传大鼠模型来解决：PINK 1的纯合敲除（KO），PINK 1是一种已知导致PD的基因突变，将这些大鼠与未受影响的对照组（野生型; WT）进行比较，并通过操纵运动条件。这种方法提供了与人类PD的直接机制联系，对当前临床使用中治疗效果的洞察，以及与发声和吞咽缺陷相关的PD中先前未探索的外周病理学的知识。采用类似于人类使用的任务和行为将最大限度地提高翻译。将在对应于早期、中期和晚期PD的年龄（6、10和14个月）对大鼠进行研究。我们的主要假设是：（1）PINK 1 KO大鼠将显示伴随外周病变的行为缺陷，其严重程度将随着疾病阶段而逐渐增加。（2）经历运动的PINK 1 KO大鼠将显示功能缺陷的预防或逆转以及外周神经肌肉病变的调节。为了解决这些假设，该提案有3个具体目标：（1）量化外周神经和肌肉的病理变化，这些神经和肌肉在PD的各个阶段介导发声和吞咽;（2）确定神经肌肉病理学如何与PD各个阶段的发声，舌强度和功能性进食缺陷相关;以及（3）确定舌头和喉咙的运动如何影响神经肌肉病理学。这一建议是及时和创新的，因为我们对PD的理解现在体现了广泛的病理学，包括肌肉和神经。拟议的研究将提供对PD中相对未探索的神经肌肉病理学的深入了解，也将是第一个研究运动如何预防或逆转舌头和喉部生物学变化的研究。我们对PINK 1 KO大鼠的系统和对照研究结合了联合收割机技术和来自行为、解剖和生理科学的理论，并提供了一个机会来了解神经肌肉病理学如何告知观察到的发声和吞咽行为变化。这种转化研究很有可能产生与重要科学和临床问题相关的有意义的发现。

 DESCRIPTION (provided by applicant): Individuals with Parkinson disease (PD) experience devastating communication and swallowing deficits that negatively impact quality of life. Recent research has shown that PD pathology is widespread, including not only central nervous system regions, but also peripheral structures such as nerves and muscles involved in communication and swallowing. However, despite these recent data, very little is known about how peripheral pathologies contribute to communication and swallowing deficits and when in the disease process these deficits emerge. Furthermore, it is unknown how behavioral treatments used clinically, such as exercise-based voice and swallow therapies, affect the manifestation of these deficits. To develop more effective treatments, a clear understanding of the progression of peripheral pathologies and the manner in which these pathologies affect communication and swallowing must be obtained. These unknowns will be addressed in the proposed research by studying a progressive, novel genetic rat model of PD: homozygous knock-out (KO) of PINK1, a gene mutation known to cause PD, comparing these rats to non-affected controls (wild type; WT), and by manipulating exercise conditions. This approach provides a direct mechanistic link to PD in humans, insight into the effects of treatments in current clinical use, and knowledge of previously unexplored peripheral pathology in PD associated with vocalization and swallowing deficits. Employing tasks and behaviors analogous to those used in humans will maximize translation. Rats will be studied at ages that correspond to early, mid, and late stage PD (6, 10 and 14 months). Our central hypotheses are: (1) PINK1 KO rats will show behavioral deficits accompanied by peripheral pathologies that will progressively increase in severity by disease stage, (2) PINK1 KO rats that undergo exercise will show prevention or reversal of functional deficits and modulation of peripheral neuromuscular pathology. To address these hypotheses, this proposal has 3 specific aims: (1) To quantify pathological changes to peripheral nerves and muscles that mediate vocalization and swallowing across stages of PD; (2) To determine how neuromuscular pathology relates to deficits in vocalization, tongue strength and functional eating across stages of PD; and (3) To determine how exercise of the tongue and larynx affects neuromuscular pathology. This proposal is timely and innovative because our understanding of PD now embodies widespread pathology that includes muscles and nerves. The proposed research will provide in-depth knowledge of neuromuscular pathology that is relatively unexplored in PD and will also be the first to examine how exercise can prevent or reverse biological changes within the tongue and larynx. Our systematic and controlled studies in the PINK1 KO rat combine techniques and theory from behavioral, anatomical, and physiological sciences and provide an opportunity to learn how neuromuscular pathologies inform observed behavioral changes in vocalization and swallowing. This translational research has a high likelihood of yielding meaningful findings related to important scientific and clinical issues.