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

基本信息

批准号：
8879656
负责人：
Lara Roberts Deruisseau
金额：
$ 36.9万
依托单位：
LE MOYNE COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879656
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 Housing Hypoxia In Vitro Incidence Individual Intellectual functioning disability Intervention Investigation Laboratories Lead Manuscripts Measures Modeling Mus Muscle Muscle Contraction Muscle Fibers Muscle Weakness Muscle function Muscle hypotonia Neuronal Dysfunction Neurons Obesity Obstruction Output Partial Pressure Pattern 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 System Testing Therapeutic Thyroid Diseases Tonsil Tonsillectomy Training Work age group aged airway obstruction base college improved insight mouse Ts65Dn multicatalytic endopeptidase complex neurophysiology next generation public health relevance relating to nervous system research study respiratory response undergraduate student

项目摘要

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）：唐氏综合症 (Ds) 是智力障碍的最常见染色体原因，由 21 号染色体基因三倍体引起，除了通常伴随唐氏综合症的并发症（包括心血管异常）外，患有唐氏综合症的人还表现出认知缺陷。、甲状腺疾病、肥胖、肌张力低下和肌肉无力、上呼吸道阻塞和睡眠呼吸暂停。我们的初步数据显示，Ts65Dn 小鼠（Ds 模型）的每分钟通气量和平均吸气流量减弱，呼吸暂停次数增加；初步数据也表明，通气不足可能是由神经引起的。 Ts65Dn 小鼠膈肌产生的力量受损，以应对疲劳的肌肉收缩，这些数据表明，观察到的呼吸模式发生了改变。 Ts65Dn 小鼠可能源自神经和肌肉起源，该提案中描述的实验将进一步检查神经和膈肌对 Ts65Dn 小鼠呼吸变化的贡献，并检查 C3-C5 中蛋白酶体（一种主要的细胞蛋白水解系统）的活性。目标#1将表征Ts65Dn小鼠的有意识通气的脊髓区域，我们将进一步表征呼吸模式的差异。 Ts65Dn 小鼠并揭示清醒 Ts65Dn 小鼠与群体对照相比动脉二氧化碳分压是否升高。目标#2 将确定 Ts65Dn 小鼠的呼吸缺陷是否与膈神经神经输出减少有关。这些实验将量化膈神经输出。我们还将评估膈核的蛋白酶体活性，以检验蛋白酶体活性在Ts65Dn 小鼠的膈肌功能将评估 Ts65Dn 小鼠的膈肌功能，这些实验将确定与群体对照小鼠相比，Ts65Dn 小鼠的膈肌是否表现出对疲劳的敏感性增加。 18 个月大，以进一步描述该模型中的衰老，由于 Ds 加速的个体表现出衰老特征，因此了解通气量如何变化非常重要。总体而言，该项目将深入了解 Ds 中调节呼吸的生理系统，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 学院的科学研究并参与其中。从事生物医学研究的本科生，以培养下一代研究人员。