Investigating Autonomic Dysfunction as an Early Pathologic Feature of Huntington’s Disease

研究自主神经功能障碍作为亨廷顿病的早期病理特征

• 批准号: 10212681
• 负责人: Jordan Schultz
• 金额: $ 18.05万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212681
• 关键词: 18 year old; Adrenergic beta-Antagonists; Adult; Age; Age of Onset; Anterior; Area; Atrophic; Autonomic Dysfunction; Autonomic nervous system; Back; Baroreflex; Biometry; Blood Pressure; Body Temperature; Brain; Brain region; Cardiovascular system; Carotid Arteries; Cerebrovascular Circulation; Cerebrovascular system; Child; Chronic; Complication; Corpus striatum structure; Disease; Disease Progression; Ensure; Equilibrium; Etiology; Exhibits; Family; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Gene therapy trial; Genes; Goals; Grant; Heart Rate; Homeostasis; Huntington Disease; Huntington gene; Huntington protein; Hypertension; Insula of Reil; Iowa; K-Series Research Career Programs; Location; Magnetic Resonance Imaging; Measures; Mentors; Mentorship; Methods; Modification; Motor; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Nervous System Physiology; Neurobiology; Neurodegenerative Disorders; Outcome; Participant; Pathologic; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacists; Pharmacology; Physiological; Plasma; Positioning Attribute; Prefrontal Cortex; Principal Investigator; Publishing; Recording of previous events; Reporting; Research; Research Personnel; Research Training; Rest; Risk; Sampling; Seeds; Signal Transduction; Spin Labels; Structure; Sympathetic Nerve Block; Sympathetic Nervous System; Symptoms; Testing; Therapeutic; Thinness; Time; Training; Training Programs; Trinucleotide Repeats; Vascular System; aged; arterial stiffness; base; beta-adrenergic receptor; blood oxygen level dependent; career; career development; cingulate cortex; experience; experimental study; gene therapy; heart rate variability; improved; mutant; neurodevelopment; neurofilament protein L; neuroimaging; new therapeutic target; novel; novel therapeutics; patient oriented; patient population; prevent; success; targeted biomarker; therapeutic target; translational scientist

Project Summary/Abstract The purpose of this Mentored Patient-Oriented Career Development Award (K23) is to support my short-term career objective of determining if dysfunction of the autonomic nervous system (ANS) is an early pathological feature of HD by quantitatively characterizing functional connections between brain regions that regulate the ANS in children with the gene expansion that causes HD using magnetic resonance imaging (MRI). I will also investigate unique physiologic measures of ANS function and early effects on the vascular system in these participants. ANS dysfunction has been described in adult patients with HD, but it has been thought that this is a secondary complication of neurodegeneration. However, I recently discovered that children carrying the HD gene expansion that causes HD (GE children) exhibit symptoms consistent with enhanced sympathetic tone decades prior to their predicted motor onset. These findings indicate that ANS dysfunction may be one of the earliest manifestations of neurodegeneration in HD. As a result, the ANS may be a therapeutic target for disease modification of HD, but more information is required. The ANS is highly regulated by cortical brain regions that comprise the Central Autonomic Network (CAN), and cortical thinning and atrophy have been well-described in HD. However, there are no published reports that have objectively characterized the integrity of the functional connections in the CAN in HD. I will perform resting-state and tasked functional MRI on GE children to characterize the function of the CAN at different stages of the disease. This experiment will test the specific hypothesis that quantitative changes in functional integrity of the CAN are apparent decades prior to the predicted motor onset of HD. Additionally, I will explore physiologic measure of ANS dysfunction including baroreflex sensitivity (BRS) and how this relates to the function of the vascular system early in the disease course of HD. Specifically, I will measure aortic stiffness and carotid artery compliance while also measuring cerebral blood flow using arterial spin labeling to test the hypotheses that relative to healthy control children, GE children will demonstrate increased aortic stiffness, decreased BRS, and decreased cerebral blood flow. These experiments will provide vital information regarding when ANS dysfunction occurs in HD, the underlying mechanisms causing the dysfunction, and if these changes have negative effects on the cardiovascular system early in the disease course. I have a unique background that positions me well to be a successful translational scientist. Further training is required in sophisticated neuroimaging methods, neurodevelopment and neurobiology, as well as biostatistics. The proposed integrated research, world-class mentorship team, and didactic training programs will ensure my short-term and long-term success. Additionally, the proposed research and training plans support my long-term career goal to be an independent translational pharmacist studying the structure and function of the brain in patients with HD to advance therapeutic strategies.

项目摘要/摘要 这个受过指导的以患者为导向的职业发展奖（K23）的目的是支持我的短期 确定自主神经系统功能障碍（ANS）是否是早期病理的职业目标 通过定量表征调节大脑区域之间功能连接的高清特征 使用磁共振成像（MRI）引起HD的基因膨胀儿童的ANS。我也会 研究ANS功能的独特生理测量和对血管系统的早期影响 参与者。 ANS功能障碍已在HD的成年患者中描述，但人们认为这是 神经退行性的继发并发症。但是，我最近发现携带高清的孩子 导致HD（GE儿童）的基因扩展表现出与增强性吻合的症状 在预测电动机发作之前的几十年。这些发现表明ANS功能障碍可能是 HD中神经退行性的最早表现。结果，ANS可能是疾病的治疗靶标 修改高清，但需要更多信息。 ANS受到皮质大脑区域的高度调节 包括中央自主网络（CAN），皮质稀疏和萎缩已被很好地描述 高清。但是，尚无主体表征功能的完整性的公开报告 罐中的连接在高清中。我将对儿童进行休息状态和任务功能性MRI 表征在疾病的不同阶段罐的功能。该实验将测试特定 假设罐的功能完整性的定量变化在预测之前是显而易见的数十年 高清运动发作。此外，我将探索ANS功能障碍（包括BaroreFlex）的生理测量 敏感性（BRS）以及这与HD疾病早期血管系统功能的关系。 具体而言，我将测量主动脉僵硬和颈动脉依从性，同时测量脑血 使用动脉自旋标记的流量来测试相对于健康对照儿童的假设，GE儿童将 证明主动脉僵硬增加，BRS降低和脑血流降低。这些实验 将提供有关何时在HD中发生ANS功能障碍的重要信息，即基础机制 引起功能障碍，如果这些变化对心血管系统产生负面影响 在疾病中。我有一个独特的背景，可以很好地成为成功的翻译 科学家。在复杂的神经影像学方法，神经发育和 神经生物学以及生物统计学。拟议的综合研究，世界一流的指导团队和 教学培训计划将确保我的短期和长期成功。此外，拟议的研究 培训计划支持我的长期职业目标，成为一个独立的翻译药剂师研究 大脑在HD患者中的结构和功能，以提高治疗策略。