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: 10620644
• 负责人: Jordan Schultz
• 金额: $ 17.94万
• 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/10620644
• 关键词: 18 year old; Adrenergic beta-Antagonists; Adult; Age; Age of Onset; Anterior; Aorta; Area; Atrophic; Autonomic Dysfunction; Autonomic nervous system; 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; 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; Physiological; Plasma; Positioning Attribute; Prefrontal Cortex; Principal Investigator; Publishing; Recording of previous events; Reporting; Research; Research Personnel; Rest; Risk; Sampling; Signal Transduction; Structure; Sympathetic Nerve Block; Sympathetic Nervous System; Symptoms; Testing; Therapeutic; Thinness; Time; Training; Training Programs; Trinucleotide Repeats; Vascular System; aged; arterial spin labeling; arterial stiffness; beta-adrenergic receptor; blood oxygen level dependent; career; career development; cingulate cortex; comparison control; 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; pharmacologic; prevent; success; therapeutic 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 这个以病人为导向的导师职业发展奖(K23)的目的是为了支持我的短期 确定自主神经系统(ANS)功能障碍是否是早期病理的职业目标 HD的特征是通过定量描述调节大脑区域之间的功能联系 使用磁共振成像(MRI)对患有导致HD的基因扩张的儿童进行ANS。我也会 研究ANS功能的独特生理指标及其对血管系统的早期影响 参与者。成人HD患者有ANS功能障碍的描述，但有人认为这是 神经退行性变的继发性并发症。然而，我最近发现，携带房屋署的儿童 导致HD(GE儿童)的基因扩展表现出与交感神经张力增强一致的症状 比他们预测的运动发作早了几十年。这些发现表明ANS功能障碍可能是 神经变性在HD中的最早表现。因此，ANS可能成为治疗疾病的靶点。 修改高清，但需要更多信息。ANS受到大脑皮质区域的高度调控， 组成中央自主神经网络(CAN)和皮质变薄和萎缩已在 高清。然而，目前还没有发表的报告客观地描述了功能性的完整性 高清模式下的易拉罐中的连接。我将对GE儿童进行静息状态和任务功能磁共振检查 描述罐头在疾病不同阶段的功能。这项实验将测试特定的 假设罐头功能完整性的数量变化比预测的要早几十年 运动性多发性硬化症。此外，我还将探讨包括压力反射在内的ANS功能障碍的生理指标。 敏感性(BRS)及其与HD病程早期血管系统功能的关系。 具体地说，我将测量主动脉硬度和颈动脉顺应性，同时也测量大脑血液。 使用动脉自旋标记来检验假设，相对于健康对照组儿童，GE儿童将 表现为主动脉僵硬增加，BRS减少，脑血流量减少。这些实验 将提供有关HD患者何时发生ANS功能障碍、潜在机制的重要信息 导致功能障碍，如果这些变化早期对心血管系统有负面影响 在病程中。我有一个独特的背景，这使我非常适合成为一名成功的翻译 科学家。需要在复杂的神经成像方法、神经发育和 神经生物学，以及生物统计学。拟议的综合研究、世界级指导团队，以及 指导性的培训计划将确保我的短期和长期成功。此外，拟议的研究 我的长期职业目标是成为一名独立的翻译药剂师，学习 研究HD患者的脑结构和功能，提出治疗策略。