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（由适用提供）：唐氏综合症（DS）是智障染色体的最常见原因，是由21个基因的三元染色而导致的。除了经常伴随DS的合并症，包括心血管异常，甲状腺疾病，肥胖，肥胖，低调和肌肉无力，上呼吸道对物体和睡眠呼吸暂停，还表现出认知缺陷。尽管睡眠呼吸暂停是患有DS的儿童和成人的普遍疾病，但尚未阐明导致这些呼吸不足的机制。我们的初步数据显示，微小的通风和平均灵感流量减弱，并且在TS65DN小鼠中增加了apneas，这是DS的模型；暗示可能具有神经元起源的通风缺陷。初步数据还表明，响应疲劳的肌肉收缩，TS65DN小鼠的diaphragm肌肉产生的力受损。总之，这些数据表明在TS65DN小鼠中观察到的改变的呼吸模式可以源自神经和肌肉的起源。该提案中描述的实验将进一步研究TS65DN小鼠呼吸改变的神经元和diaphragm肌肉的贡献，并检查蛋白酶体（一种主要的细胞蛋白水解系统）在脊髓的C3-C5区域的活性，作为一种潜在的呼吸改变机制。 AIM＃1将表征TS65DN小鼠中有意识的通风。我们将进一步表征TS65DN小鼠的呼吸模式的差异，并揭示CO2的动脉部分压力是否在有意识的TS65DN小鼠中升高，而colony对菌落对照。 AIM＃2将确定呼吸是否定义了TS65DN小鼠的呼吸是否与phrenic神经的神经元输出降低有关。这些实验将量化phrenic爆发放大器，以测量神经元对呼吸的贡献。我们还将评估Phrenic核us的蛋白酶体活性，以检验TS65DN小鼠中蛋白酶体活性较低的假设。 AIM＃3将评估TS65DN小鼠中的隔膜肌肉功能。与菌落对照相比，这些实验将确定来自TS65DN小鼠的隔膜是否表现出增加体外疲劳的敏感性。所有目标都将在3个月，12个月和18个月大时研究小鼠，以进一步描述该模型的衰老。由于具有DS的个体表现出加速衰老的特征，因此了解通风如何随着TS65DN小鼠的年龄增长而变化非常重要。总体而言，该项目将提供对调节DS呼吸的物理系统的见解，目的是改善这种情况的人的生活质量。这些实验将支持Le Moyne学院的科学，并让本科生参加生物医学研究，以培训下一代研究人员。