Investigation into neural and muscular components of breathing in Down Syndrome

唐氏综合症呼吸的神经和肌肉成分的研究

• 批准号: 9475010
• 负责人: Lara Roberts Deruisseau
• 金额: $ 20.33万
• 依托单位: LE MOYNE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9475010
• 关键词: Action Potentials; Address; Adenoidal structure; Adenoidectomy; Adult; Age; Age-Months; Aging; Apnea; Area; Attenuated; Behavioral; Biochemical; Biological Assay; Biology; Biomedical Research; Brain; Breathing; Carbon Dioxide; Cardiovascular Abnormalities; Cardiovascular system; Cell Nucleus; Central Sleep Apnea; Characteristics; Child; Chromosomes; Chromosomes, Human, Pair 21; Cognitive; Cognitive deficits; Collaborations; Comorbidity; Conscious; Craniofacial Abnormalities; Data; Developmental Disabilities; Disease; Down Syndrome; Elderly; Environmental air flow; Excision; Exhibits; Face; Fatigue; Foundations; Functional disorder; Future; Genes; Genetic; Healthcare; Hypoxia; Impairment; In Vitro; Incidence; Individual; Intellectual functioning disability; Intervention; Investigation; Laboratories; Lead; Manuscripts; Measures; Modeling; Morphology; Mus; Muscle; Muscle Contraction; Muscle Fatigue; Muscle Fibers; Muscle Weakness; Muscle function; Muscle hypotonia; Neuronal Dysfunction; Neurons; Obesity; Obstruction; Output; Partial Pressure; Pattern; Periodicity; Persons; Phenotype; Physiological; Population; Predisposition; Production; Proteins; Public Health; Publishing; Quality of life; Recovery; Recurrence; Reporting; Research Personnel; Resistance; Respiration Disorders; Respiratory Diaphragm; Respiratory Insufficiency; Science; Skeletal Muscle; Sleep Apnea Syndromes; Spinal Cord; Structure of phrenic nerve; Suggestion; System; Testing; Therapeutic; Thyroid Diseases; Tonsil; Tonsillectomy; Training; Work; age group; aged; airway obstruction; base; college; experimental study; improved; insight; mouse Ts65Dn; multicatalytic endopeptidase complex; neurophysiology; next generation; public health relevance; relating to nervous system; respiratory; response; undergraduate student

 DESCRIPTION (provided by applicant): Down syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Persons with Ds demonstrate cognitive deficits in addition to co- morbidities that often accompany Ds, including cardiovascular abnormalities, thyroid disease, obesity, hypotonia and muscle weakness, upper airway obstructions, and sleep apnea. Although sleep apnea is a prevalent disorder in children and adults with Ds, the mechanisms responsible for these breathing deficits have not been elucidated. Our preliminary data reveal attenuated minute ventilation and mean inspiratory flow, and an increased number of apneas in Ts65Dn mice, a model of Ds; suggestive of ventilation deficits that may have a neural origin. Preliminary data also suggest impaired force production of diaphragm muscle from Ts65Dn mice in response to fatiguing muscle contractions. Together, these data suggest that the altered breathing patterns observed in Ts65Dn mice could be derived from neural and muscular origins. The experiments described in this proposal will further examine neural and diaphragm muscle contributions to breathing alterations in Ts65Dn mice and examine the activity of the proteasome, a major cellular proteolytic system, in the C3-C5 region of the spinal cord as a potential mechanism of breathing alterations. Aim #1 will characterize conscious ventilation in Ts65Dn mice. We will further characterize differences in the breathing pattern of Ts65Dn mice and reveal if arterial partial pressures of CO2 are elevated in conscious Ts65Dn mice vs. colony controls. Aim #2 will determine if breathing deficits of Ts65Dn mice are associated with reduced neural output of the phrenic nerve. These experiments will quantify the phrenic burst amplitude to measure the neural contribution to breathing. We will also assess proteasome activity of the phrenic nucleus to test the hypothesis that proteasome activity will be lower in Ts65Dn mice. Aim #3 will assess diaphragm muscle function in Ts65Dn mice. These experiments will determine if diaphragm from Ts65Dn mice exhibits increased susceptibility to fatigue in vitro compared to diaphragm from colony controls. All aims will study mice at 3 months, 12 months and 18 months of age to further describe aging in this model. Since individuals with Ds demonstrate characteristics of accelerated aging it will be important to know how ventilation changes with advancing age in Ts65Dn mice. Overall, this project will provide insight into the physiological systems that modulate breathing in Ds with the objective of improving the quality of life of persons with this condition. These experiments will support the sciences at Le Moyne College and engage undergraduate students in biomedical research to train the next generation of researchers.

 描述（由申请人提供）：唐氏综合征（Ds）是智力残疾的最常见染色体原因，由21号染色体基因的三倍引起。患有Ds的人除了通常伴随Ds的共病之外还表现出认知缺陷，包括心血管异常、甲状腺疾病、肥胖、张力减退和肌无力、上呼吸道阻塞和睡眠呼吸暂停。虽然睡眠呼吸暂停是一种普遍的疾病，在儿童和成人与Ds，机制负责这些呼吸缺陷尚未阐明。我们的初步数据显示，衰减分钟通气量和平均吸气流量，并在Ts 65 Dn小鼠，一个模型的Ds呼吸暂停的数量增加，提示通气功能障碍，可能有神经起源。初步数据还表明Ts 65 Dn小鼠的膈肌响应于疲劳肌肉收缩的力产生受损。总之，这些数据表明，在Ts 65 Dn小鼠中观察到的呼吸模式改变可能来自神经和肌肉来源。本提案中描述的实验将进一步检查神经和膈肌对Ts 65 Dn小鼠呼吸改变的贡献，并检查脊髓C3-C5区域中蛋白酶体（一种主要的细胞蛋白水解系统）的活性，作为呼吸改变的潜在机制。目的#1将表征Ts 65 Dn小鼠中的有意识通气。我们将进一步表征Ts 65 Dn小鼠呼吸模式的差异，并揭示清醒Ts 65 Dn小鼠与群体对照相比动脉CO2分压是否升高。目的#2将确定Ts 65 Dn小鼠的呼吸缺陷是否与膈神经的神经输出减少相关。这些实验将量化膈爆发振幅，以测量神经对呼吸的贡献。我们还将评估膈核的蛋白酶体活性，以检验Ts 65 Dn小鼠中蛋白酶体活性较低的假设。目的#3将评估Ts 65 Dn小鼠中的膈肌功能。这些实验将确定Ts 65 Dn小鼠的膈肌与群体对照的膈肌相比是否表现出体外疲劳易感性增加。所有目标将研究3月龄、12月龄和18月龄的小鼠，以进一步描述该模型中的衰老。由于Ds个体表现出加速老化的特征，因此了解Ts 65 Dn小鼠的通气量如何随着年龄的增长而变化是很重要的。总体而言，该项目将提供对调节Ds呼吸的生理系统的深入了解，目的是改善患有这种疾病的人的生活质量。这些实验将支持Le Moyne College的科学，并让本科生参与生物医学研究，以培养下一代研究人员。