Heart and vascular responses across the lifespan in Ts65Dn mice, a model of Down syndrome

Ts65Dn 小鼠（唐氏综合症模型）整个生命周期中心脏和血管的反应

• 批准号: 9896413
• 负责人: Lara Roberts Deruisseau
• 金额: $ 27.36万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-06-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896413
• 关键词: Activities of Daily Living; Age; Age-Months; Aging; Animal Model; Aorta; Applications Grants; Atherosclerosis; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Baroreflex; Biological; Biology; Birth; Blood Pressure; Blood Vessels; Cardiac Output; Cardiovascular Models; Cardiovascular Physiology; Cardiovascular alteration; Cardiovascular system; Characteristics; Chromosome 21; Clinical; Cognition; Cognitive deficits; Congenital Heart Defects; Conscious; Coupled; Data; Dementia; Developmental Disabilities; Diastolic blood pressure; Dose; Down Syndrome; Elderly; Endothelium; Exercise; Female; Future; Genes; Genetic; Healthcare; Heart; Heart Abnormalities; Heart Rate; Hypotension; In Vitro; Individual; Intellectual functioning disability; Isometric Exercise; Life Expectancy; Longevity; Measures; Mediating; Mesenteric Arteries; Mesentery; Modeling; Monitor; Morale; Mus; Nitroprusside; Operative Surgical Procedures; Parasympathetic Nervous System; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Phenylephrine; Physiologic pulse; Physiological; Physiology; Population; Preparation; Public Health; Pulmonary Hypertension; Quality of life; Reaction; Regulation; Reporting; Rest; Series; System; Tail; Telemetry; Testing; Time; Vasodilation; Ventricular Function; Wild Type Mouse; Work; age group; arterial stiffness; base; blood pressure reduction; blood pressure regulation; circadian; comorbidity; endothelial dysfunction; experimental study; heart function; heart rate variability; improved; in vivo; insight; male; mouse Ts65Dn; pressure; response; sex; stressor; vascular endothelial dysfunction; virtual; Activities of Daily Living; Age; Age-Months; Aging; Animal Model; Aorta; Applications Grants; Atherosclerosis; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Baroreflex; Biological; Biology; Birth; Blood Pressure; Blood Vessels; Cardiac Output; Cardiovascular Models; Cardiovascular Physiology; Cardiovascular alteration; Cardiovascular system; Characteristics; Chromosome 21; Clinical; Cognition; Cognitive deficits; Congenital Heart Defects; Conscious; Coupled; Data; Dementia; Developmental Disabilities; Diastolic blood pressure; Dose; Down Syndrome; Elderly; Endothelium; Exercise; Female; Future; Genes; Genetic; Healthcare; Heart; Heart Abnormalities; Heart Rate; Hypotension; In Vitro; Individual; Intellectual functioning disability; Isometric Exercise; Life Expectancy; Longevity; Measures; Mediating; Mesenteric Arteries; Mesentery; Modeling; Monitor; Morale; Mus; Nitroprusside; Operative Surgical Procedures; Parasympathetic Nervous System; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Phenylephrine; Physiologic pulse; Physiological; Physiology; Population; Preparation; Public Health; Pulmonary Hypertension; Quality of life; Reaction; Regulation; Reporting; Rest; Series; System; Tail; Telemetry; Testing; Time; Vasodilation; Ventricular Function; Wild Type Mouse; Work; age group; arterial stiffness; base; blood pressure reduction; blood pressure regulation; circadian; comorbidity; endothelial dysfunction; experimental study; heart function; heart rate variability; improved; in vivo; insight; male; mouse Ts65Dn; pressure; response; sex; stressor; vascular endothelial dysfunction; virtual

ABSTRACT 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 including cardiovascular alterations and pulmonary hypertension. Lower blood pressure at rest and in response to exercise and other stressors are prevalent in Ds. The attenuated cardiovascular reactions to activities of daily living in Ds are autonomically mediated, but likely include other factors such as endothelial dysfunction. These cardiovascular findings are complicated by the fact that Ds is protected from atherosclerosis. Therefore, the mechanisms responsible for cardiovascular alterations in Ds are multifaceted in this population. At this time there is not an appropriately developed cardiovascular model to investigate these important clinical concerns, although a trisomic animal model does exist. Our robust preliminary data reveal attenuated mean arterial blood pressure, diastolic blood pressure and systolic blood pressure in restrained Ts65Dn mice, a model of Ds. Freely moving Ts65Dn mice have lower heart rate than wild-type (WT). Taken together, these data suggest the altered cardiovascular patterns observed in Ts65Dn mice may be representative of people with Ds. This exploratory grant application aims to verify, via a series of physiological experiments, that the Ts65Dn mouse is an appropriate model to study heart and blood pressure differences in Ds. The experiments described in this proposal will further examine cardiovascular alterations in Ts65Dn mice through conscious and reduced preparations, including autonomic nervous system contributions and endothelial dysregulation as a potential mechanism of attenuated vascular tone and cardiac output. Specific Aim 1 will compare the cardiovascular profile and vascular physiology of WT and Ts65Dn mice at 3, 6 and 12 months of age. Blood pressure and heart rate will be quantified across the circadian cycle via radiotelemetry, and we will further distinguish possible mechanistic differences in autonomic control of blood pressure with pharmacological blockade of the sympathetic and parasympathetic nervous system in conscious mice. Arterial stiffness will be quantified in anesthetized mice using pulse wave velocity, and heart rate variability will be used to monitor autonomic tone in both conscious and anesthetized experiments. Arterial isometric tension using an in vitro setup will compare endothelial dependent and independent vasodilation of aorta and mesenteric artery. Specific Aim 2 will quantify baroreflex sensitivity and cardiac function with in vivo pressure-volume loops in WT and Ts65Dn mice. All aims will study male and female mice at 3 months, 6 months and 12 months of age to further describe aging and sex as biological variables in this model. Since individuals with Ds demonstrate characteristics of accelerated aging it will be important to know how heart function and blood pressure responses change with advancing age in WT vs. Ts65Dn. Overall, this project will provide insight into cardiovascular regulation in Ds with the objective of improving the quality of life of persons with this condition. !

抽象的 唐氏综合症（DS）是最常见的智障染色体原因，是由 染色体21个基因的三分一式化。 DS的人除了共同表现出认知缺陷 病因，包括心血管改变和肺动脉高压。降低休息时的血压 响应运动和其他压力源在DS中很普遍。衰减的心血管反应 DS中日常生活的活动是自主介导的，但可能包括其他因素，例如内皮 功能障碍。这些心血管的发现使DS受到保护不受 动脉粥样硬化。因此，在DS中导致心血管改变的机制是多方面的 这个人口。目前，没有适当开发的心血管模型来研究这些模型 尽管确实存在三化动物模型，但重要的临床问题。我们强大的初步数据显示 抑制的平均动脉血压，舒张压和收缩压 TS65DN小鼠，DS的模型。自由移动的TS65DN小鼠的心率低于野生型（WT）。拍摄 总之，这些数据表明在TS65DN小鼠中观察到的心血管模式发生了改变 DS人的代表。该探索性赠款应用程序旨在通过一系列生理验证 实验，TS65DN小鼠是研究心脏和血压差异的合适模型 DS。该提案中描述的实验将进一步检查TS65DN小鼠的心血管改变 通过有意识和减少的准备，包括自主神经系统的贡献和 内皮失调是减弱血管张力和心输出量的潜在机制。具体的 AIM 1将比较3、6和12的WT和TS65DN小鼠的心血管谱和血管生理学 几个月。血压和心率将通过radiotelemetry在整个昼夜节律中进行量化， 我们将进一步区分与血压自主控制的可能机械差异 有意识小鼠的交感神经和副交感神经系统的药理阻滞。动脉 使用脉冲波速度在麻醉小鼠中量化刚度，将使用心率变异性 在有意识和麻醉实验中监测自主语调。使用A的动脉等距张力 体外设置将比较主动脉和肠系膜动脉的内皮依赖性和独立的血管舒张。 特定的目标2将用体内压力 - 体积循环量化压力反射灵敏度和心脏功能 和TS65DN小鼠。所有目标将在3个月，6个月零12个月大的时候研究男性和雌性小鼠 在此模型中，进一步将衰老和性别描述为生物学变量。由于患有DS的人证明了 加速衰老的特征很重要的是要知道心脏功能和血压如何 响应随着wt与TS65DN的年龄的发展而变化。总体而言，该项目将提供有关 DS中的心血管调节，目的是改善这种情况的人的生活质量。 呢